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PMC:7463108 JSONTXT 18 Projects

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Id Subject Object Predicate Lexical cue
T1 0-65 Sentence denotes Opioid and neuroHIV Comorbidity – Current and Future Perspectives
T2 67-75 Sentence denotes Abstract
T3 76-290 Sentence denotes With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS).
T4 291-479 Sentence denotes Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity.
T5 480-687 Sentence denotes However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood.
T6 688-913 Sentence denotes In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels.
T7 914-1165 Sentence denotes Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone.
T8 1166-1368 Sentence denotes These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity.
T9 1369-1528 Sentence denotes Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV.
T10 1529-1596 Sentence denotes Graphical Abstract Blood-brain barrier and the neurovascular unit.
T11 1597-1775 Sentence denotes With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain.
T12 1776-1928 Sentence denotes Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.
T13 1930-1938 Sentence denotes Overview
T14 1940-1957 Sentence denotes The Opioid Crisis
T15 1958-2031 Sentence denotes Opioid abuse in the United States (U.S.) has reached catastrophic levels.
T16 2032-2187 Sentence denotes According to the latest World Drug Report, 53.4 million people worldwide used opioids in 2017, which is 56% higher than in the previous year (UNODC 2019a).
T17 2188-2346 Sentence denotes North America remains the region with the highest non-medical use of opioids with a staggering 4% of the population aged 15–64 using opioids (UNODC 2019a, c).
T18 2347-2551 Sentence denotes In 2017, the burden of opioid use in the U.S. had accounted for 42 million healthy years of life lost due to premature death and disability (Institute for Health Metrics and Evaluation 2017; UNODC 2019a).
T19 2552-2709 Sentence denotes During 2017, there were 70,237 overdose related deaths, out of which 47,600 (67.8%) were caused by opioids, which was a 12% increase from 2016 (Scholl et al.
T20 2710-2729 Sentence denotes 2018; UNODC 2019c).
T21 2730-2868 Sentence denotes The Centers of Disease Control and Prevention (CDC) reports that on average 130 Americans die from an opioid overdose each day (CDC 2017).
T22 2869-2931 Sentence denotes Due to the constant rise in deaths involving opioids, the U.S.
T23 2932-3018 Sentence denotes Government declared the opioid crisis/epidemic a public health emergency in 2017 (U.S.
T24 3019-3065 Sentence denotes Department of Health and Human Services 2017).
T25 3066-3271 Sentence denotes Injection drug use increases the likelihood of contracting human immunodeficiency virus (HIV) and drug abuse and HIV have long been described as interrelated epidemics (Swan 1997; Leshner 1998; Nath et al.
T26 3272-3284 Sentence denotes 1999, 2002).
T27 3285-3424 Sentence denotes Despite this understanding, opioid use disorder (OUD) and HIV remain a huge public health concern (Strathdee and Beyrer 2015; Peters et al.
T28 3425-3431 Sentence denotes 2016).
T29 3432-3609 Sentence denotes In fact, the opioid crisis is seen as a major roadblock in several aspects of public health, including thwarting the goal of eliminating HIV within the next decade (Fauci et al.
T30 3610-3639 Sentence denotes 2019; Lerner and Fauci 2019).
T31 3640-3737 Sentence denotes OUD is also likely to exacerbate many negative aspects of the COVID-19 pandemic (Alexander et al.
T32 3738-3794 Sentence denotes 2020; Becker and Fiellin 2020; NIDA 2020; Wakeman et al.
T33 3795-3801 Sentence denotes 2020).
T34 3802-4164 Sentence denotes Not only are individuals with OUD more vulnerable to SARS-CoV-2 and liable to spread the infection, social-distancing practices create isolation, despair, and economic hardships, heightening opioid abuse (with inherent respiratory depression depending on the amount of tolerance developed) and the probability of overdose (Becker and Fiellin 2020; Wakeman et al.
T35 4165-4171 Sentence denotes 2020).
T36 4172-4421 Sentence denotes By virtue of its greater safety profile and decreased likelihood for abuse (Bell and Strang 2020), the use of buprenorphine via telemedicine has become advantageous for managing OUD during the COVID-19 pandemic (Leppla and Gross 2020; Samuels et al.
T37 4422-4482 Sentence denotes 2020) but presents new challenges (Khatri and Perrone 2020).
T38 4483-4593 Sentence denotes The current opioid crisis did not happen quickly; in fact, it has been described as occurring in three phases.
T39 4594-4689 Sentence denotes The first phase began in the late 1990s with an increase in the number of prescription opioids.
T40 4690-4814 Sentence denotes This led to overdose deaths that were attributable to natural and semi-synthetic opioids, such as methadone (Kolodyny et al.
T41 4815-4831 Sentence denotes 2015; CDC 2017).
T42 4832-4935 Sentence denotes The second phase began in 2010 in which heroin took the lead as the principal cause of overdose deaths.
T43 4936-5105 Sentence denotes The most recent, third wave, began in 2013 in which highly potent synthetic opioids, such as fentanyl and its analogs became the main cause of mortality (Kolodyny et al.
T44 5106-5122 Sentence denotes 2015; CDC 2017).
T45 5123-5246 Sentence denotes The entry of fentanyl and its analogs into the clandestine market has changed the dynamics of the opioid market in the U.S.
T46 5247-5470 Sentence denotes The synthetic opioids, such as fentanyl, are several orders of magnitude more potent than morphine, easily smuggled, and frequently and inconsistently mixed with lower quality drugs increasing the probability of overdosing.
T47 5471-5547 Sentence denotes According to the National Forensic Laboratory Information System of the U.S.
T48 5548-5718 Sentence denotes Drug Enforcement Administration (DEA), fentanyl accounted for one-third of the illicit opioids seized in 2017 (UNODC 2019c) and has become a global problem (UNODC 2019b).
T49 5720-5755 Sentence denotes The Pathophysiology of Opioid Abuse
T50 5756-5851 Sentence denotes The effects of opioid abuse on the central nervous system (CNS) have been extensively examined.
T51 5852-6109 Sentence denotes Immediate effects of opioids result in decreased levels of consciousness, sedation (Collett 1998; Thompson 2000; Indelicato and Portenoy 2002), drowsiness, and sleep disturbances (Moore and Dimsdale 2002; Bourne and Mills 2004; Qureshi and Lee-Chiong 2004).
T52 6110-6205 Sentence denotes While acute opioid exposure can impair cognition in healthy subjects (Lawlor 2002; Ersek et al.
T53 6206-6302 Sentence denotes 2004), enduring cognitive and psychomotor deficits occur with chronic opioid use (Sjogren et al.
T54 6303-6322 Sentence denotes 2000; Dublin et al.
T55 6323-6343 Sentence denotes 2015; Roberts et al.
T56 6344-6364 Sentence denotes 2018; Wollman et al.
T57 6365-6386 Sentence denotes 2019; Serafini et al.
T58 6387-6598 Sentence denotes 2020), including altered pain perception (opioid-induced hyperalgesia), dysregulated reward/saliency processing, hyperkatifeia, and epigenetic changes, which can persist years following abstinence (Ersche et al.
T59 6599-6618 Sentence denotes 2006; Browne et al.
T60 6619-6625 Sentence denotes 2020).
T61 6626-6887 Sentence denotes The behavioral changes seen with long-term opioid use are accompanied by lasting structural and epigenetic (e.g., altered DNA methylation and expression of non-coding RNAs) alterations in brain regions implicated in mood, reward, and motivation (Upadhyay et al.
T62 6888-6907 Sentence denotes 2010; Dublin et al.
T63 6908-6976 Sentence denotes 2015; Volkow and Morales 2015; Koob and Volkow 2016; Serafini et al.
T64 6977-6983 Sentence denotes 2020).
T65 6984-7158 Sentence denotes Up to 90% of post-mortem tissues sampled from opiate abusers display brain edema (Buttner 2011), astrogliosis and microgliosis especially in the hippocampus (Oehmichen et al.
T66 7159-7232 Sentence denotes 1996), white matter, and subcortical regions at autopsy (Tomlinson et al.
T67 7233-7253 Sentence denotes 1999; Anthony et al.
T68 7254-7274 Sentence denotes 2005; Buttner et al.
T69 7275-7304 Sentence denotes 2006; Buttner and Weis 2006).
T70 7305-7493 Sentence denotes The reactive gliosis is accompanied by increases in proinflammatory cytokines and inflammatory mediators, including TNF-α, IL-1β, and nitric oxide synthase (NOS) (Dyuizen and Lamash 2009).
T71 7494-7764 Sentence denotes Opiates especially drive the enhanced activation of heme-oxygenase, NOS, and cyclic GMP-dependent-protein kinase (Liang and Clark 2004) and production of reactive nitrogen species (RNS) such as peroxynitrite (Salvemini 2009), and resultant nitrosative damage (Zou et al.
T72 7765-7771 Sentence denotes 2011).
T73 7772-7853 Sentence denotes Nitrosative damage is an important endpoint for opiate exposure (Pasternak et al.
T74 7854-8022 Sentence denotes 1995; Liang and Clark 2004; Salvemini 2009) and key site of convergence for the oxidative stress accompanying HIV protein exposure (Hauser and Knapp 2014; McLane et al.
T75 8023-8029 Sentence denotes 2018).
T76 8030-8360 Sentence denotes For delayed heroin overdose death after a survival period of 5 h or more, studies report neurovascular disorders, hypoxic ischemic leukoencephalopathy, and region-specific atrophy with neuronal losses that can include the hippocampal formation, the cerebellar Purkinje cell layer and olivary nucleus (Protass 1971; Ginsberg et al.
T77 8361-8383 Sentence denotes 1976; Gosztonyi et al.
T78 8384-8441 Sentence denotes 1993), as well as other areas (Buttner 2011; Cadet et al.
T79 8442-8448 Sentence denotes 2014).
T80 8449-8646 Sentence denotes Loss of neurons and synaptic connections is supported by postmortem reports of smaller mean relative volumes in various brain regions in individuals with OUD, including cortical areas (Danos et al.
T81 8647-8667 Sentence denotes 1998; Pezawas et al.
T82 8668-8707 Sentence denotes 1998), the basal ganglia (Muller et al.
T83 8708-8752 Sentence denotes 2015, 2019), prefrontal cortex (Cadet et al.
T84 8753-8791 Sentence denotes 2014), and hypothalamus (Muller et al.
T85 8792-8798 Sentence denotes 2018).
T86 8799-8856 Sentence denotes Interestingly, leukoencephalopathy, atrophy (Cadet et al.
T87 8857-9023 Sentence denotes 2014), and increased hyperphosphorylated tau-containing neurofibrillary tangles are reported with chronic opiate abuse compared to age-matched controls (Ramage et al.
T88 9024-9044 Sentence denotes 2005; Anthony et al.
T89 9045-9064 Sentence denotes 2010; Kovacs et al.
T90 9065-9071 Sentence denotes 2015).
T91 9072-9385 Sentence denotes Glycogen synthase kinase 3 α or β (GSK-3α/β; the pan antibody used in this study does not discern α from β isoforms) and/or cyclin-dependent kinase-5 (Cdk-5) are increased in the frontal and temporal cortices, the locus coeruleus, and the hippocampus, respectively, and correlate with microgliosis (Anthony et al.
T92 9386-9392 Sentence denotes 2010).
T93 9393-9528 Sentence denotes Further, more prolonged use increases the risk of accelerated age-related and even Alzheimer’s-like pathological changes (Ramage et al.
T94 9529-9549 Sentence denotes 2005; Anthony et al.
T95 9550-9569 Sentence denotes 2010; Kovacs et al.
T96 9570-9615 Sentence denotes 2015) and cognitive impairment (Gruber et al.
T97 9616-9622 Sentence denotes 2007).
T98 9623-9903 Sentence denotes Moreover, heroin use is associated with symmetric T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions of the CNS using magnetic resonance imaging (MRI), which coincide with increased microgliosis and inflammation at the same sites (Upadhyay et al.
T99 9904-9921 Sentence denotes 2010; Bora et al.
T100 9922-9938 Sentence denotes 2012; Qiu et al.
T101 9939-9957 Sentence denotes 2013; Alaee et al.
T102 9958-9973 Sentence denotes 2014; Li et al.
T103 9974-9992 Sentence denotes 2016; Shrot et al.
T104 9993-9999 Sentence denotes 2017).
T105 10000-10203 Sentence denotes Although a few studies have started to examine opiate-HIV interactions in white matter (see below), we predict that the interactive effects on myelin dysregulation will significantly worsen CNS outcomes.
T106 10204-10344 Sentence denotes Preclinical studies indicate opioid-induced neuroimmune signaling alter the saliency of opioid reward and physical dependence (Narita et al.
T107 10345-10368 Sentence denotes 2006; Hutchinson et al.
T108 10369-10381 Sentence denotes 2008, 2009).
T109 10382-10547 Sentence denotes Direct injections of astrocyte-conditioned medium containing cytokines into the nucleus accumbens (NAc) increase morphine conditioned place preference (Narita et al.
T110 10548-10554 Sentence denotes 2006).
T111 10555-10716 Sentence denotes Drugs reported to selectively attenuate glial inflammation block morphine conditioned place preference and attenuate symptoms of opioid withdrawal (Narita et al.
T112 10717-10740 Sentence denotes 2006; Hutchinson et al.
T113 10741-10757 Sentence denotes 2009; Liu et al.
T114 10758-10912 Sentence denotes 2010). μ (MOR), δ (DOR), and κ (KOR) opioid receptors are expressed by subsets of astrocytes and microglia (Stiene-Martin and Hauser 1991; Eriksson et al.
T115 10913-10939 Sentence denotes 1992; Stiene-Martin et al.
T116 10940-10960 Sentence denotes 1993; Ruzicka et al.
T117 10961-10981 Sentence denotes 1995; Gurwell et al.
T118 10982-11001 Sentence denotes 1993; Hauser et al.
T119 11002-11030 Sentence denotes 1996; Turchan-Cholewo et al.
T120 11031-11050 Sentence denotes 2008; Maduna et al.
T121 11051-11214 Sentence denotes 2018) and are involved in opioid tolerance and dependence to varying degrees (Kieffer and Gaveriaux-Ruff 2002; Berger and Whistler 2010; Morgan and Christie 2011).
T122 11215-11327 Sentence denotes Despite some reports of morphine triggering immune activation via Toll-like receptor 4 (TLR4) (Terashvili et al.
T123 11328-11351 Sentence denotes 2008; Hutchinson et al.
T124 11352-11403 Sentence denotes 2010; Coller and Hutchinson 2012; Hutchinson et al.
T125 11404-11425 Sentence denotes 2012; Theberge et al.
T126 11426-11448 Sentence denotes 2013; Lacagnina et al.
T127 11449-11530 Sentence denotes 2017) by binding to a myeloid differentiation protein-2 intermediary (Wang et al.
T128 11531-11725 Sentence denotes 2012), this is contrary to the typical actions of opiates, which by themselves (and in the absence of a priming event such as HIV co-exposure) tend to suppress immune function (Eisenstein 2019).
T129 11726-11880 Sentence denotes A vast majority of the immune, antinociceptive, and other physiological effects of opioids are mediated by opioid receptors per se and not TLR4 (Hu et al.
T130 11881-11902 Sentence denotes 2011; Fukagawa et al.
T131 11903-11923 Sentence denotes 2013; Stevens et al.
T132 11924-11945 Sentence denotes 2013; Mattioli et al.
T133 11946-11969 Sentence denotes 2014; Eisenstein 2019).
T134 11970-12110 Sentence denotes Overall, the findings indicate that immune signaling plays a critical role in the pathophysiology of OUD and associated physical dependence.
T135 12111-12289 Sentence denotes How opioids effect neuroHIV, as well as how opioid abuse and dependence are altered by neuroHIV or whether opioid-HIV interactions result in a unique disease state are discussed.
T136 12291-12383 Sentence denotes HIV Neuropathology in the Context of Opioid Use Disorder – Clinical and Preclinical Evidence
T137 12385-12440 Sentence denotes Preclinical and Clinical Findings—a Complicated Picture
T138 12441-12555 Sentence denotes People infected with HIV (PWH) with OUD have an increased incidence of neuroHIV and CNS complications (Bell et al.
T139 12556-12573 Sentence denotes 1998; Nath et al.
T140 12574-12607 Sentence denotes 1999, 2000a, 2002; Anthony et al.
T141 12608-12626 Sentence denotes 2008; Meyer et al.
T142 12627-12645 Sentence denotes 2013; Smith et al.
T143 12646-12652 Sentence denotes 2014).
T144 12653-12729 Sentence denotes Injection drug use increases the probability of contracting HIV (Nath et al.
T145 12730-12797 Sentence denotes 1999) and opioid drugs intrinsically alter the pathogenesis of HIV.
T146 12798-12935 Sentence denotes PWH who develop intractable pain syndromes related to peripheral neuropathies often receive opioid drugs for treatment (Mirsattari et al.
T147 12936-12954 Sentence denotes 1999; Denis et al.
T148 12955-12961 Sentence denotes 2019).
T149 12962-13137 Sentence denotes PWH who misuse opioids are more likely to undertake risky sexual behavior and are less likely to adhere to combined antiretroviral (ARV) therapy (cART) regimens (Lemons et al.
T150 13138-13144 Sentence denotes 2019).
T151 13145-13308 Sentence denotes Opioid receptors are widely expressed on immune cells and opioids can modulate immune function (Donahoe and Falek 1988; Plotnikoff 1988; Rouveix 1992; Adler et al.
T152 13309-13347 Sentence denotes 1993; Carr and Serou 1995; Carr et al.
T153 13348-13366 Sentence denotes 1996; Sheng et al.
T154 13367-13388 Sentence denotes 1997; Banerjee et al.
T155 13389-13409 Sentence denotes 2011; Purohit et al.
T156 13410-13493 Sentence denotes 2012), which typically (but not always) result in immune suppression (Wybran et al.
T157 13494-13516 Sentence denotes 1979; McDonough et al.
T158 13517-13567 Sentence denotes 1980, 1981; Donahoe and Falek 1988; Donahoe et al.
T159 13568-13586 Sentence denotes 1991; Falek et al.
T160 13587-13606 Sentence denotes 1991; Novick et al.
T161 13607-13624 Sentence denotes 1991; Chao et al.
T162 13625-13647 Sentence denotes 1996a; Peterson et al.
T163 13648-13692 Sentence denotes 1998; Rogers and Peterson 2003; Stein et al.
T164 13693-13709 Sentence denotes 2003; Roy et al.
T165 13710-13730 Sentence denotes 2006; Rittner et al.
T166 13731-13737 Sentence denotes 2008).
T167 13738-13994 Sentence denotes The “opiate cofactor hypothesis” proposes opioids contribute directly to the pathogenesis of acquired immune deficiency syndrome (AIDS) (Donahoe and Vlahov 1998), in part, because MOR activation can increase HIV replication in immune cells (Peterson et al.
T168 13995-14028 Sentence denotes 1990, 1992, 1993, 1999; Ho et al.
T169 14029-14035 Sentence denotes 2003).
T170 14036-14110 Sentence denotes Furthermore, MOR and HIV co-receptors, including both CCR5 (El-Hage et al.
T171 14111-14128 Sentence denotes 2013; Yuan et al.
T172 14129-14148 Sentence denotes 2013; Arnatt et al.
T173 14149-14180 Sentence denotes 2016) and CXCR4 (Pitcher et al.
T174 14181-14296 Sentence denotes 2014) can interact via convergent downstream signaling and perhaps via direct molecular interactions (Rogers et al.
T175 14297-14342 Sentence denotes 2000; Rogers and Peterson 2003; Steele et al.
T176 14343-14360 Sentence denotes 2003; Chen et al.
T177 14361-14378 Sentence denotes 2004; Song et al.
T178 14379-14398 Sentence denotes 2011; Arnatt et al.
T179 14399-14405 Sentence denotes 2016).
T180 14406-14486 Sentence denotes MOR-CCR5 or CXCR4 interactions are highly contextual and can promote (Guo et al.
T181 14487-14506 Sentence denotes 2002; Steele et al.
T182 14507-14539 Sentence denotes 2003) or inhibit (Strazza et al.
T183 14540-14637 Sentence denotes 2014) HIV expression, depending on the nature and duration of exposure (see Fig. 9; Berman et al.
T184 14638-14678 Sentence denotes 2006) and cell type involved (Kim et al.
T185 14679-14685 Sentence denotes 2018).
T186 14686-14790 Sentence denotes Depending on the outcome measure, Tat expression reduces morphine’s efficacy and potency (Fitting et al.
T187 14791-14814 Sentence denotes 2012, 2016; Hahn et al.
T188 14815-14821 Sentence denotes 2016).
T189 14822-14996 Sentence denotes Antagonizing CCR5 with maraviroc reinstates morphine potency in an antinociceptive assay and restores physical dependence in Tat exposed, morphine-tolerant mice (Gonek et al.
T190 14997-15003 Sentence denotes 2018).
T191 15004-15109 Sentence denotes Epidemiological studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al.
T192 15110-15132 Sentence denotes 2004; Meijerink et al.
T193 15133-15145 Sentence denotes 2014, 2015).
T194 15146-15240 Sentence denotes In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al.
T195 15241-15253 Sentence denotes 1998, 2002).
T196 15254-15425 Sentence denotes In Indonesian injection heroin abusers who lacked access to cART, CD4 counts (a measure of HIV progression) were reduced compared to PWH not using heroin (Meijerink et al.
T197 15426-15432 Sentence denotes 2014).
T198 15433-15786 Sentence denotes However, with the introduction of cART, the clinical picture has significantly changed with a 50% decline in the rate of death from AIDS, reduced incidence of opportunistic infections and HIVE, and a 40–50% decrease in the incidence of HIV-associated dementia (HAD), the most severe form of HIV-associated neurocognitive disorders (HAND) (Maschke et al.
T199 15787-15808 Sentence denotes 2000; McArthur et al.
T200 15809-15828 Sentence denotes 2010; Saylor et al.
T201 15829-15835 Sentence denotes 2016).
T202 15836-15996 Sentence denotes Nevertheless, chronic opiate exposure (which almost always is confounded by the use of other illicit and legal drugs) in PWH can worsen neuroHIV (Anthony et al.
T203 15997-16014 Sentence denotes 2005; Bell et al.
T204 16015-16035 Sentence denotes 2006; Anthony et al.
T205 16036-16092 Sentence denotes 2008) and cognitive impairment (Rodriguez Salgado et al.
T206 16093-16142 Sentence denotes 2006; Martin-Thormeyer and Paul 2009; Byrd et al.
T207 16143-16161 Sentence denotes 2011; Smith et al.
T208 16162-16181 Sentence denotes 2014; Martin et al.
T209 16182-16200 Sentence denotes 2018; Rubin et al.
T210 16201-16301 Sentence denotes 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al.
T211 16302-16324 Sentence denotes 1991; Applebaum et al.
T212 16325-16353 Sentence denotes 2010) or HAND (Martin et al.
T213 16354-16360 Sentence denotes 2019).
T214 16361-16444 Sentence denotes Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al.
T215 16445-16511 Sentence denotes 2004), neuropathology (including increased tauopathy; Smith et al.
T216 16512-16551 Sentence denotes 2014), CNS inflammation (Anthony et al.
T217 16552-16576 Sentence denotes 2005, 2008; Smith et al.
T218 16577-16620 Sentence denotes 2014), and neurocognition (Applebaum et al.
T219 16621-16638 Sentence denotes 2009; Byrd et al.
T220 16639-16657 Sentence denotes 2011; Meyer et al.
T221 16658-16724 Sentence denotes 2013) including deficits in memory and working memory (Byrd et al.
T222 16725-16731 Sentence denotes 2011).
T223 16732-16887 Sentence denotes Table 1 gives an overview on reported interactive effects of HIV and opioids in some of the clinical and preclinical CNS studies referenced in this review.
T224 16888-16929 Sentence denotes Table 1 Clinical and preclinical findings
T225 16930-17002 Sentence denotes Major effects HIV pathogena ARV Opioids Outcome Model system Citation(s)
T226 17003-17028 Sentence denotes Clinical findings (human)
T227 17029-17080 Sentence denotes HIV progression and/or ARV adherence HIV cART • SUD
T228 17081-17136 Sentence denotes • Prescription opioids for pain • ↑ Viral load with SUD
T229 17137-17154 Sentence denotes • ↓ ARV adherence
T230 17155-17226 Sentence denotes • ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al.
T231 17227-17232 Sentence denotes 2019)
T232 17233-17275 Sentence denotes HIV cART OUD • ↓ Lasting viral suppression
T233 17276-17330 Sentence denotes • ↓ Adherence to cART for 3 years Human (Lemons et al.
T234 17331-17336 Sentence denotes 2019)
T235 17337-17406 Sentence denotes HIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al.
T236 17407-17412 Sentence denotes 2014)
T237 17413-17436 Sentence denotes HIV encephalitis (HIVE)
T238 17437-17517 Sentence denotes HIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells
T239 17518-17566 Sentence denotes • ↑ HIV p24 Human, postmortem brain (Bell et al.
T240 17567-17572 Sentence denotes 1998)
T241 17573-17604 Sentence denotes Microglial activation HIV • ARV
T242 17605-17706 Sentence denotes • ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al.
T243 17707-17712 Sentence denotes 2014)
T244 17713-17722 Sentence denotes HIV • ARV
T245 17723-17819 Sentence denotes • ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al.
T246 17820-17825 Sentence denotes 2002)
T247 17826-17863 Sentence denotes HIV No info Drug use • ↑ MHC class II
T248 17864-17912 Sentence denotes • ↑ CD68 Human, postmortem brain (Anthony et al.
T249 17913-17918 Sentence denotes 2005)
T250 17919-18010 Sentence denotes HIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD
T251 18011-18074 Sentence denotes • No effect of IDU on CD68 Human, postmortem brain (Byrd et al.
T252 18075-18080 Sentence denotes 2012)
T253 18081-18207 Sentence denotes Plasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al.
T254 18208-18213 Sentence denotes 2004)
T255 18214-18309 Sentence denotes HIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS
T256 18310-18366 Sentence denotes • ↑ CCR5 expression in CD4 cells Human (Meijerink et al.
T257 18367-18372 Sentence denotes 2015)
T258 18373-18434 Sentence denotes HIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates
T259 18435-18511 Sentence denotes • ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al.
T260 18512-18517 Sentence denotes 1993)
T261 18518-18682 Sentence denotes Aberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only
T262 18683-18733 Sentence denotes • No HIV effect/interaction Human (Jankovic et al.
T263 18734-18739 Sentence denotes 1991)
T264 18740-18833 Sentence denotes Learning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope
T265 18834-18880 Sentence denotes • ↓ Delayed recall Human, female (Meyer et al.
T266 18881-18886 Sentence denotes 2013)
T267 18887-18933 Sentence denotes HIV cART Reported heroin use • ↓ Recall memory
T268 18934-18971 Sentence denotes • ↓ Working memory Human (Byrd et al.
T269 18972-18977 Sentence denotes 2011)
T270 18978-19056 Sentence denotes HIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy
T271 19057-19096 Sentence denotes • ↓ Delayed recall Human (Concha et al.
T272 19097-19102 Sentence denotes 1997)
T273 19103-19195 Sentence denotes Neuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al.
T274 19196-19201 Sentence denotes 2010)
T275 19202-19351 Sentence denotes Cognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al.
T276 19352-19357 Sentence denotes 2018)
T277 19358-19364 Sentence denotes Memory
T278 19365-19450 Sentence denotes Cognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+
T279 19451-19525 Sentence denotes • ↓ Spatial and verbal response times in women, irrespective of HIV status
T280 19526-19581 Sentence denotes • ↑ Response time with cocaine use Human (Martin et al.
T281 19582-19587 Sentence denotes 2018)
T282 19588-19715 Sentence denotes Visual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone
T283 19716-19762 Sentence denotes • No HIV effect/interaction Human (Bauer 1998)
T284 19763-19865 Sentence denotes Transmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)
T285 19866-19912 Sentence denotes HIV cART OST • ↓ Frequency of heroin injection
T286 19913-19944 Sentence denotes • ↑ On ARV Human (Pettes et al.
T287 19945-19950 Sentence denotes 2010)
T288 19951-20024 Sentence denotes Motor and visual function HIV No info OST • ↓ Digital Finger-Tapping test
T289 20025-20075 Sentence denotes • ↓ Visual motor pursuit Human (Silberstein et al.
T290 20076-20081 Sentence denotes 1993)
T291 20082-20173 Sentence denotes ARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al.
T292 20174-20179 Sentence denotes 2018)
T293 20180-20248 Sentence denotes PENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−
T294 20249-20279 Sentence denotes • ↓ DRD2L HIV+ vs. HIVE & HIV−
T295 20280-20305 Sentence denotes • ↓ DRD2L correlates with
T296 20306-20369 Sentence denotes ↑ cognitive performance Human, post mortem brain (Gelman et al.
T297 20370-20375 Sentence denotes 2012)
T298 20376-20546 Sentence denotes OPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol & tobacco (but not opiate) use Human (Crystal et al.
T299 20547-20552 Sentence denotes 2012)
T300 20553-20655 Sentence denotes HIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al.
T301 20656-20661 Sentence denotes 2012)
T302 20662-20710 Sentence denotes HIV No info MOR-1K expression • ↑ MOR-1K in HIVE
T303 20711-20814 Sentence denotes • ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al.
T304 20815-20820 Sentence denotes 2014)
T305 20821-20959 Sentence denotes OPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al.
T306 20960-20965 Sentence denotes 2013)
T307 20966-21093 Sentence denotes Sensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al.
T308 21094-21099 Sentence denotes 2010)
T309 21100-21137 Sentence denotes Preclinical in vivo findings (animal)
T310 21138-21271 Sentence denotes HIV entry into the brain Mixture of SIV17-EFr, SHIVKU_1B, SHIV89.6P No Morphine (5 mg/kg i.m., b.i.d., ≤ 56 weeks) • ↑ CSF viral load
T311 21272-21344 Sentence denotes • ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al.
T312 21345-21350 Sentence denotes 2006)
T313 21351-21425 Sentence denotes SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells
T314 21426-21444 Sentence denotes • ↑ CSF viral load
T315 21445-21516 Sentence denotes • ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al.
T316 21517-21523 Sentence denotes 2011).
T317 21524-21673 Sentence denotes Viral load and HIV progression Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine (5 mg/kg, i.m., t.i.d., 20 weeks) • ↑ Viral load; ↓ CD4 counts
T318 21674-21740 Sentence denotes • ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al.
T319 21741-21768 Sentence denotes 2007; Perez-Casanova et al.
T320 21769-21774 Sentence denotes 2008)
T321 21775-21861 Sentence denotes SIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine
T322 21862-21927 Sentence denotes (5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts
T323 21928-21984 Sentence denotes • tat evolution—inverse correlation with SIV progression
T324 21985-22066 Sentence denotes • ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al.
T325 22067-22073 Sentence denotes 2006b)
T326 22074-22106 Sentence denotes nef • ↑ Viral load; ↓ CD4 counts
T327 22107-22185 Sentence denotes • ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al.
T328 22186-22192 Sentence denotes 2006a)
T329 22193-22225 Sentence denotes env • ↑ Viral load; ↓ CD4 counts
T330 22226-22298 Sentence denotes • ↑ env evolution (V4 region) correlates with SIV progression + morphine
T331 22299-22358 Sentence denotes • ↑ env evolution in CSF with morphine (Rivera-Amill et al.
T332 22359-22371 Sentence denotes 2007, 2010b)
T333 22372-22469 Sentence denotes vpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality
T334 22470-22537 Sentence denotes • ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al.
T335 22538-22543 Sentence denotes 2013)
T336 22544-22665 Sentence denotes Neuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal
T337 22666-22705 Sentence denotes • ↓ PSD95 during chronic and withdrawal
T338 22706-22723 Sentence denotes • ↑ Sphingomyelin
T339 22724-22769 Sentence denotes • ↓ Ceramide Mouse, gp120 tgb (Bandaru et al.
T340 22770-22775 Sentence denotes 2011)
T341 22776-22883 Sentence denotes HIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al.
T342 22884-22889 Sentence denotes 2012)
T343 22890-22893 Sentence denotes SIV
T344 22894-23005 Sentence denotes HIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV
T345 23006-23138 Sentence denotes • ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al.
T346 23139-23144 Sentence denotes 2012)
T347 23145-23297 Sentence denotes Synaptic transmission Tat1–86 No Morphine ex vivo (1 μM) to the bath ↓ mIPSC frequency Mouse, male and female, PFC slices, ex vivo (Xu and Fitting 2016)
T348 23298-23311 Sentence denotes SIVmacR71/17E
T349 23312-23390 Sentence denotes Tat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)
T350 23391-23441 Sentence denotes • Morphine in vitro • SIV ↑ Synaptic protein HSPA5
T351 23442-23488 Sentence denotes • Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;
T352 23489-23495 Sentence denotes Human,
T353 23496-23549 Sentence denotes SH-SY5Y neuroblastoma cells in vitro (Pendyala et al.
T354 23550-23555 Sentence denotes 2015)
T355 23556-23670 Sentence denotes White matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions
T356 23671-23743 Sentence denotes • ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al.
T357 23744-23750 Sentence denotes 2008),
T358 23751-23865 Sentence denotes CNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time
T359 23866-23916 Sentence denotes • ↑ Creatine in white matter (SIV + morphine only)
T360 23917-23974 Sentence denotes • ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al.
T361 23975-23980 Sentence denotes 2011)
T362 23981-24107 Sentence denotes Neuroinflammation Tat1–86 No Morphine (10 mg/kg i.p., b.i.d., 5 days) ↑ Iba1+ 3-NT+ microglia Mouse, Tat tg, males (Zou et al.
T363 24108-24113 Sentence denotes 2011)
T364 24114-24132 Sentence denotes Chemokines Tat1–72
T365 24133-24243 Sentence denotes (25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5
T366 24244-24277 Sentence denotes • ↑ CCL2 in macrophages/microglia
T367 24278-24362 Sentence denotes • CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al.
T368 24363-24369 Sentence denotes 2008a)
T369 24370-24502 Sentence denotes Cytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection
T370 24503-24524 Sentence denotes • ↑ TNFα, IL-6, CCL2,
T371 24525-24600 Sentence denotes • ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al.
T372 24601-24606 Sentence denotes 2012)
T373 24607-24695 Sentence denotes MOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al.
T374 24696-24701 Sentence denotes 2007)
T375 24702-24782 Sentence denotes MOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)
T376 24783-24946 Sentence denotes • Morphine, DAMGO (ex vivo) ↓ [35S]GTPγS binding in NAc Shell, CPu, amygdala, PFC, but not hippocampus, with morphine in Tat mice Mouse, Tat tg, males (Hahn et al.
T377 24947-24952 Sentence denotes 2016)
T378 24953-25149 Sentence denotes Neuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)
T379 25150-25195 Sentence denotes • ↑ CPP and cytokines (24 h after withdrawal)
T380 25196-25271 Sentence denotes • Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al.
T381 25272-25277 Sentence denotes 2018)
T382 25278-25396 Sentence denotes Neuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia
T383 25397-25446 Sentence denotes • ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al.
T384 25447-25452 Sentence denotes 2018)
T385 25453-25612 Sentence denotes Morphine efficacy, potency Tat1–86 No Morphine (acute, 2–8 mg/kg s.c.) ↓ Antinociceptive potency and efficacy (tail flick) Mouse, Tat tg, males (Fitting et al.
T386 25613-25618 Sentence denotes 2012)
T387 25619-25731 Sentence denotes Morphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance
T388 25732-25792 Sentence denotes • ↓ Physical dependence Mouse, Tat tg, males (Fitting et al.
T389 25793-25798 Sentence denotes 2016)
T390 25799-25980 Sentence denotes Locomotor function Tat1–86 No Oxycodone (0–10 mg/kg, i.p., 15 min prior behavioral assay) ↑ Locomotor activity, center entries (open field) Mouse, Tat tg, females (Salahuddin et al.
T391 25981-25986 Sentence denotes 2020)
T392 25987-26116 Sentence denotes SIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al.
T393 26117-26122 Sentence denotes 2016)
T394 26123-26230 Sentence denotes Tat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al.
T395 26231-26236 Sentence denotes 2020)
T396 26237-26383 Sentence denotes BBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al.
T397 26384-26389 Sentence denotes 2019)
T398 26390-26526 Sentence denotes Immune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine
T399 26527-26642 Sentence denotes • ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)
T400 26643-26667 Sentence denotes ARV accumulation Tat DTG
T401 26668-26671 Sentence denotes ABC
T402 26672-26857 Sentence denotes 3TC Morphine (2 mg/day, s.c.. osmotic pump, 5 days) ↓ Dolutegravir and abacavir, but no change in lamivudine in brains of morphine-treated animals Mouse, Tat tg females (Leibrand et al.
T403 26858-26863 Sentence denotes 2019)
T404 26864-26996 Sentence denotes Circadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al.
T405 26997-27002 Sentence denotes 2008)
T406 27003-27116 Sentence denotes aassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant
T407 27117-28163 Sentence denotes ABC, abacavir; ARV, antiretroviral(s); BBB, blood-brain barrier; b.i.d., twice a day; Brd4, Bromodomain-containing protein 4; CPu, caudate-putamen; CNS, central nervous system; CPP, conditioned place preference; CM, conditioned medium; CSF, cerebrospinal fluid; DAMGO [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DRD2L, type 2 dopamine receptor; DTG, dolutegravir; HIVE, HIV encephalitis (typically seen pre-cART); HSPA5, heat shock 70-kDa protein A 5; IDU, injection drug use; i.m., intramuscularly; i.p., intraperitoneal; Iba1, ionized calcium-binding adapter molecule 1; 3TC, lamivudine; MHC class II, major histocompatibility class II; mIPSC, miniature inhibitory postsynaptic currents; MOR, μ-opioid receptor; No info, information not provided or uncertain; OST, opioid substitution therapy; OUD, opioid use disorder; PFC, prefrontal cortex; PENK, preproenkephalin; q.d., once a day; q.i.d., four times a day; ROS, reactive oxygen species; s.c., subcutaneous; SUD, substance use disorder; tg, transgenic; t.i.d., three times a day; ZDV, zidovudine
T408 28164-28319 Sentence denotes For practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes.
T409 28320-28764 Sentence denotes With deference toward the excellent studies we excluded: (1) on opioid and HIV effects on peripheral blood mononuclear cells (PBMCs), or on isolated lymphocytes and monocytes, not directly related to the central nervous system or BBB; (2) on HIV or opioid and ARV interactions in the peripheral nervous system; and (3) studies not directly examining opioid-HIV interactions (irrespective of whether a positive or negative interaction was found)
T410 28765-28996 Sentence denotes Although translational, “bench-to-bedside”, research is important, reverse-translational approaches and multiple preclinical models are essential to better understand complex disease and improve established therapies (Singer 2019).
T411 28997-29181 Sentence denotes Evidence suggests that HIV compartmentalizes within the CNS early during the course of the infection establishing a separate reservoir harboring “intact proviral” HIV (Churchill et al.
T412 29182-29201 Sentence denotes 2016; Bruner et al.
T413 29202-29262 Sentence denotes 2019) within resident neural cell populations (Bednar et al.
T414 29263-29286 Sentence denotes 2015; Sturdevant et al.
T415 29287-29308 Sentence denotes 2015; Veenhuis et al.
T416 29309-29365 Sentence denotes 2019) and perivascular macrophages (Fischer-Smith et al.
T417 29366-29384 Sentence denotes 2001; Burdo et al.
T418 29385-29418 Sentence denotes 2013; Rappaport and Volsky 2015).
T419 29419-29719 Sentence denotes Preclinical studies assessing opioid interactions with HIV or viral proteins permit mechanistic understanding of how particular CNS cell types, including neurons, astroglia, and microglia are affected and contribute to accentuating effects of opiates on neuroHIV, which are discussed in detail below.
T420 29721-29793 Sentence denotes Cellular and Molecular Interactions in Astroglia, Microglia, and Neurons
T421 29794-29910 Sentence denotes Prior reviews have outlined how opiate drugs likely exacerbate neuroHIV pathology in neurons and glia (Hauser et al.
T422 29911-29950 Sentence denotes 2005; Dutta and Roy 2012; Hauser et al.
T423 29951-29969 Sentence denotes 2012; Reddy et al.
T424 29970-30009 Sentence denotes 2012; Hauser and Knapp 2014; Liu et al.
T425 30010-30030 Sentence denotes 2016a; Murphy et al.
T426 30031-30104 Sentence denotes 2019) including in the enteric nervous system (Galligan 2015; Meng et al.
T427 30105-30111 Sentence denotes 2015).
T428 30112-30401 Sentence denotes Opioid-HIV pathophysiological interactions are complex and differ depending on the timing and duration of co-exposure, the pharmacology of the opioid drug involved, the cell types and brain regions targeted, host and viral genetics, and are highly contextual (Hauser and Knapp 2014, 2018).
T429 30402-30519 Sentence denotes A summary of the cellular and molecular interactions in various CNS cell types is also reviewed in detail in Table 2.
T430 30520-30574 Sentence denotes Table 2 Cellular and molecular interactions (in vitro)
T431 30575-30658 Sentence denotes Major effects HIV pathogena ARV Opioids Outcome Model system (in vitro) Citation(s)
T432 30659-30669 Sentence denotes Mixed-Glia
T433 30670-30703 Sentence denotes HIV expression HIV No • Dynorphin
T434 30704-30713 Sentence denotes • U50,488
T435 30714-30750 Sentence denotes (KOR agonists) • ↑ HIV-1 expression,
T436 30751-30881 Sentence denotes • Dynorphin (KOR agonist) ↑ TNF-α, IL-6 mRNA and protein Human fetal neural cells, HIV-infected promonocyte (U1) line (Chao et al.
T437 30882-30887 Sentence denotes 1995)
T438 30888-30909 Sentence denotes HIVSF162 No • U50,488
T439 30910-30919 Sentence denotes • U69,593
T440 30920-30936 Sentence denotes • Dynorphin1–17;
T441 30937-30951 Sentence denotes (KOR agonists)
T442 30952-31061 Sentence denotes • Morphine • KOR agonists ± TNF-α differentially ↓ HIV p24 Human, primary mixed neurons and glia (Chao et al.
T443 31062-31068 Sentence denotes 1998a)
T444 31069-31114 Sentence denotes Chemokines Tat1–86 No Morphine • ↑ CCL5, CCL2
T445 31115-31146 Sentence denotes • ↑ [Ca2+]i (Beclin1 dependent)
T446 31147-31203 Sentence denotes • ↓ Autophagy Mouse, primary mixed glia (Lapierre et al.
T447 31204-31209 Sentence denotes 2018)
T448 31210-31272 Sentence denotes HIVSF162 (R5) No Morphine • ↑ HIV-1 Tat-induced LTR expression
T449 31273-31337 Sentence denotes • ↑ CCR5 expression (inhibited by bivalent ligand in astrocytes)
T450 31338-31346 Sentence denotes • ↑ IL-6
T451 31347-31397 Sentence denotes • ↑ CCL5 Human, primary mixed glia (El-Hage et al.
T452 31398-31403 Sentence denotes 2013)
T453 31404-31588 Sentence denotes Glial restricted precursors: survival & MOR, DOR, KOR expression Tat1–72 No Morphine (acting via DOR and/or KOR) • ↑ Caspase-3 activation & ↑ cell death by Tat or morphine via DOR, KOR
T454 31589-31662 Sentence denotes • No opioid-Tat interactions Mouse, primary glial precursors (Buch et al.
T455 31663-31668 Sentence denotes 2007)
T456 31669-31692 Sentence denotes MOR expression in NPCs;
T457 31693-31783 Sentence denotes NPC survival and developmental fate Tat1–72 No Morphine • MOR expressed by subsets of NPCs
T458 31784-31866 Sentence denotes • ↑ Astrocyte and immature glial death Mouse, primary mixed glia (Khurdayan et al.
T459 31867-31872 Sentence denotes 2004)
T460 31873-32055 Sentence denotes MOR and CCR5 interactions Tat1–86 (from HIVIIIB) No Morphine • ↓ Neuronal survival via CCR5 activation in glia (rescued by BDNF treatment) Mouse, primary neurons and glia (Kim et al.
T461 32056-32061 Sentence denotes 2018)
T462 32062-32125 Sentence denotes HIV infectivity MOR-CCR5 dimerization HIVSF162 (R5) No Morphine
T463 32126-32248 Sentence denotes CCR5-MOR bivalent ligand 1b • MOR-CCR5 bivalent ligand blocks HIV infection in astroglia, but not microglia, with morphine
T464 32249-32409 Sentence denotes • MOR-CCR5 bivalent ligand blocks the fusion of HIV gp160 and CCR5-CD4-expressing HEK cells Human, primary astrocytes and microglia; HEK-293T cells (Yuan et al.
T465 32410-32429 Sentence denotes 2013; Arnatt et al.
T466 32430-32435 Sentence denotes 2016)
T467 32436-32583 Sentence denotes HIV expression and maturational fate of neurons and astroglia HIVBaL (R5) No Morphine • ↑ HIV p24 and ↑ Tat mRNA levels with morphine after 21 days
T468 32584-32711 Sentence denotes • ↓ Proliferation of neural progenitors; ↑ astroglial and ↑ neuronal differentiation Human, neural progenitors (Balinang et al.
T469 32712-32717 Sentence denotes 2017)
T470 32718-32728 Sentence denotes Astrocytes
T471 32729-32781 Sentence denotes HIV expression HIVSF162 (R5) No Morphine • ↑ HIV p24
T472 32782-32834 Sentence denotes • ↑ CCL2 Human, primary astrocytes (Rodriguez et al.
T473 32835-32840 Sentence denotes 2017)
T474 32841-32895 Sentence denotes Toll-like receptor (TLR) expression/function • Tat1–72
T475 32896-32956 Sentence denotes • gp120 No Morphine • ↑ TLR2 with Tat, Tat + morphine, gp120
T476 32957-33033 Sentence denotes • ↓ TLR9 with Tat, morphine, gp120 Mouse, primary astrocytes (El-Hage et al.
T477 33034-33040 Sentence denotes 2011a)
T478 33041-33086 Sentence denotes Chemokines Tat1–72 No Morphine • ↑ CCL5, CCL2
T479 33087-33095 Sentence denotes • ↑ IL-6
T480 33096-33149 Sentence denotes • ↑ [Ca2+]i Mouse, primary astrocytes (El-Hage et al.
T481 33150-33155 Sentence denotes 2005)
T482 33156-33184 Sentence denotes Tat1–72 No Morphine • ↑ CCL2
T483 33185-33193 Sentence denotes • ↑ CCL5
T484 33194-33260 Sentence denotes • ↑ Microglial migration Mouse, primary astrocytes (El-Hage et al.
T485 33261-33267 Sentence denotes 2006a)
T486 33268-33313 Sentence denotes Tat1–72 No Morphine • ↑ CCL2, ↑ IL-6, ↑ TNF-α
T487 33314-33325 Sentence denotes • ↑ [Ca2+]i
T488 33326-33365 Sentence denotes • ↑ NF-κB trafficking and transcription
T489 33366-33453 Sentence denotes • No interaction / acceleration with morphine Mouse, primary astrocytes (El-Hage et al.
T490 33454-33460 Sentence denotes 2008b)
T491 33461-33491 Sentence denotes Tat No • U50,488 (KOR agonist)
T492 33492-33535 Sentence denotes • Nor-BNI (KOR antagonist) • U50,488 ↓ CCL2
T493 33536-33593 Sentence denotes • U50,488 ↓ NF-κB Human, primary astrocytes (Sheng et al.
T494 33594-33599 Sentence denotes 2003)
T495 33600-33637 Sentence denotes N/A No Morphine • ↑ CCR5, CCR3, CXCR2
T496 33638-33721 Sentence denotes • ↓ IL-8, CCL4 Human, astrocytoma U87 cell line, primary astrocytes (Mahajan et al.
T497 33722-33727 Sentence denotes 2002)
T498 33728-33737 Sentence denotes • Tat1–86
T499 33738-33881 Sentence denotes • gp120IIIB No Morphine Regional differences in cytokine and ROS production —differed for each insult Mouse, primary astrocytes (Fitting et al.
T500 33882-33888 Sentence denotes 2010a)
T501 33889-33933 Sentence denotes Oxidative stress / damage Tat1–72 No • DPDPE
T502 33934-33942 Sentence denotes • SNC-80
T503 33943-34057 Sentence denotes (DOR agonists) DOR agonists ↓ Tat-induced oxidative stress Human derived brain cell line (SK-N-SH) (Wallace et al.
T504 34058-34063 Sentence denotes 2006)
T505 34064-34108 Sentence denotes Inflammation, maturation /plasticity • Tat86
T506 34109-34270 Sentence denotes • Tat101 No Morphine ↓ β-catenin signaling and variably decreases TrkB, BDNF, and NLRP1 mRNA in fetal astrocytes b Human, U87MG and fetal astrocytes (Chen et al.
T507 34271-34276 Sentence denotes 2020)
T508 34277-34286 Sentence denotes Microglia
T509 34287-34335 Sentence denotes HIV replication HIVSF162 (R5) No • Endomorphin-1
T510 34336-34351 Sentence denotes • Endomorphin-2
T511 34352-34420 Sentence denotes (MOR agonists) • ↑ HIV p24 with endomorphin-1, but not endomorphin-2
T512 34421-34510 Sentence denotes • Endomorphin-1 acts via MOR, but not DOR / KOR Human, primary microglia (Peterson et al.
T513 34511-34516 Sentence denotes 1999)
T514 34517-34593 Sentence denotes HIVSF162 (R5) No Morphine ↑ HIV p24 Human, primary microglia (El-Hage et al.
T515 34594-34599 Sentence denotes 2014)
T516 34600-34650 Sentence denotes HIVSF162 (R5) No • U50,488; U69,593 (KOR agonists)
T517 34651-34716 Sentence denotes • Dynorphin Al-13 ↓ HIV p24 Human, primary microglia (Chao et al.
T518 34717-34723 Sentence denotes 1996b)
T519 34724-34739 Sentence denotes • HIVJR-FL (R5)
T520 34740-34781 Sentence denotes • gp120 No β-endorphin • ↑ HIV expression
T521 34782-34817 Sentence denotes • ↑ HIV p24 (14-day post infection)
T522 34818-34881 Sentence denotes • gp120 ↑ IL-1, TNF, IL-6 Human, fetal microglia (Sundar et al.
T523 34882-34887 Sentence denotes 1995)
T524 34888-34931 Sentence denotes HIVSF162 No • 8-CAC, U50,488 (KOR agonists)
T525 34932-34989 Sentence denotes • Cocaine • KOR agonist ↓ p24; blocked by KOR antagonists
T526 34990-35077 Sentence denotes • KOR agonist negates cocaine-induced ↑ HIV Human, fetal brain microglia (Gekker et al.
T527 35078-35083 Sentence denotes 2004)
T528 35084-35111 Sentence denotes HIVSF162 No OPRL1 antisense
T529 35112-35188 Sentence denotes Nociceptin / orphanin FQ (OPRL1 agonist) • OPRL1 antisense (and sense) ↓ p24
T530 35189-35284 Sentence denotes • Nociceptin, no effect on p24 Human, fetal brain microglia and mixed neurons/glia (Chao et al.
T531 35285-35291 Sentence denotes 1998b)
T532 35292-35317 Sentence denotes HIV expression • HIVSF162
T533 35318-35380 Sentence denotes • Tat ZDV U50,488 (KOR agonist) • ↓ p24 on day 14 with U50,488
T534 35381-35408 Sentence denotes • ↓ Neurotoxicity (U50,488)
T535 35409-35490 Sentence denotes • ↓ Quinolinate by microglia Human, fetal microglia and neural cells (Chao et al.
T536 35491-35496 Sentence denotes 2000)
T537 35497-35550 Sentence denotes Chemokines and Cytokines Tat1–72 No Morphine • ↑ CCR5
T538 35551-35568 Sentence denotes • ↑ CD11b, ↑ CD40
T539 35569-35595 Sentence denotes • ↑ TNF-α, ↑ IL-6, ↑ IP-10
T540 35596-35654 Sentence denotes • ↑ iNOS Mouse, BV-2 and primary microglia (Bokhari et al.
T541 35655-35660 Sentence denotes 2009)
T542 35661-35718 Sentence denotes MOR signaling Tat1–72 No Morphine • ↑ MOR (intracellular)
T543 35719-35787 Sentence denotes • ↑ MOR mRNA Mouse, N9 and primary microglia (Turchan-Cholewo et al.
T544 35788-35793 Sentence denotes 2008)
T545 35794-35870 Sentence denotes Oxidative Stress Tat1–72 No Morphine • ↑ ROS [O2− (DHE), ↑ HO2•, H2O2 (DCF)]
T546 35871-35948 Sentence denotes • ↑ Protein carbonyls Mouse, N9 and primary microglia (Turchan-Cholewo et al.
T547 35949-35954 Sentence denotes 2009)
T548 35955-36110 Sentence denotes Glutamate release Tat1–72 No Morphine ↑ Glutamate release via ↑ xc− cystine-glutamate antiporter expression/function Mouse, primary microglia (Gupta et al.
T549 36111-36116 Sentence denotes 2010)
T550 36117-36124 Sentence denotes Neurons
T551 36125-36231 Sentence denotes HIV expression HIV No Morphine ↑ HIV expression Human derived, SH-SY5Y neuroblastoma cells (Squinto et al.
T552 36232-36237 Sentence denotes 1990)
T553 36238-36293 Sentence denotes Homeostasis and Injury Tat1–86 No Morphine • ↑ [Ca2+]i,
T554 36294-36304 Sentence denotes • ↑ [Na+]i
T555 36305-36340 Sentence denotes • ↓ ΔΨm (mitochondrial) instability
T556 36341-36406 Sentence denotes • ↑ Dendritic degeneration Mouse, primary neurons (Fitting et al.
T557 36407-36413 Sentence denotes 2014a)
T558 36414-36479 Sentence denotes Mitochondrial inner membrane potential and ROS • Tat1–86, Tat1–72
T559 36480-36754 Sentence denotes • gp120 No Morphine ↑ ΔΨm instability and oxidative stress ↑ with Tat + morphine, ↑ neuroprotection with allopregnanolone Human, primary neurons ; mouse, striatal medium spiny neurons; mouse, striatal medium spiny neurons, SH-SY5Y neuroblastoma cells (Turchan-Cholewo et al.
T560 36755-36773 Sentence denotes 2006; Paris et al.
T561 36774-36779 Sentence denotes 2020)
T562 36780-36895 Sentence denotes Neuronal survival Tat1–86 No Morphine • ↓ Neuronal survival from Tat + morphine and ↓ glial CX3CL1 rescued by CX3CL
T563 36896-37001 Sentence denotes • CX3CL1 (fractalkine) regulates microglial motility Mouse, primary neurons and mixed glia (Suzuki et al.
T564 37002-37007 Sentence denotes 2011)
T565 37008-37045 Sentence denotes Tat1–86 No Morphine • ↓ Proliferation
T566 37046-37067 Sentence denotes • ↑ ERK1/2 activation
T567 37068-37083 Sentence denotes • ↑ p53 and p21
T568 37084-37153 Sentence denotes • ↓ Cyclin D1 and Akt levels Human, neuronal precursors (Malik et al.
T569 37154-37159 Sentence denotes 2014)
T570 37160-37210 Sentence denotes Tat1–72, Tat1–86 No Morphine • ↓ Neuronal survival
T571 37211-37370 Sentence denotes • ↑ Neuronal survival with ibudilast (AV411) (inhibiting glial NF-κB blocks Tat ± morphine neurotoxicity) Mouse, primary neurons and mixed glia (Gurwell et al.
T572 37371-37391 Sentence denotes 2001; El-Hage et al.
T573 37392-37397 Sentence denotes 2014)
T574 37398-37437 Sentence denotes White matter/oligodendroglial pathology
T575 37438-37563 Sentence denotes Changes in OL survival and morphology Tat1–86 No Morphine (25 mg pellet, 7 days); morphine (in vitro) • ↑ Degeneration of OLs
T576 37564-37584 Sentence denotes • ↑ TUNEL reactivity
T577 37585-37651 Sentence denotes • ↑ Caspase-3 activation Mouse, Tat tg; primary OLs (Hauser et al.
T578 37652-37657 Sentence denotes 2009)
T579 37658-37704 Sentence denotes Blood-brain barrier and the neurovascular unit
T580 37705-37767 Sentence denotes BBB model integrity and function Tat1–86 No Morphine • ↑ TNF-α
T581 37768-37776 Sentence denotes • ↑ IL-8
T582 37777-37784 Sentence denotes • ↓TEER
T583 37785-37805 Sentence denotes • ↑ JAM-2 expression
T584 37806-37909 Sentence denotes • ↑ Monocyte transmigration with CCL5 Human, using primary BMVEC and primary astrocytes (Mahajan et al.
T585 37910-37915 Sentence denotes 2008)
T586 37916-37944 Sentence denotes ARV accumulation Tat1–86 DTG
T587 37945-37948 Sentence denotes FTC
T588 37949-38038 Sentence denotes TFV Morphine • ↓ Intracellular ARV concentrations Human, primary astrocytes (Patel et al.
T589 38039-38044 Sentence denotes 2019)
T590 38045-38069 Sentence denotes HIV-1 strain differences
T591 38070-38166 Sentence denotes Neuronal Survival Tat1–86 (clades B & C) No Morphine • ↓ Neuronal survival via MOR on mixed glia
T592 38167-38188 Sentence denotes • ↑ ROS in astrocytes
T593 38189-38280 Sentence denotes • ↑ Iba1 and 3-NT microglia with morphine Mouse, primary neurons and mixed glia (Zou et al.
T594 38281-38286 Sentence denotes 2011)
T595 38287-38298 Sentence denotes • gp120IIIB
T596 38299-38313 Sentence denotes • gp120MN (X4)
T597 38314-38537 Sentence denotes • gp120ADA (R5) No Morphine ↓ Neuronal survival in presence of glia with gp120MN and transiently with gp120IIIB (X4), not R5-tropic gp120, in combination with morphine Mouse, primary neurons and mixed glia (Podhaizer et al.
T598 38538-38543 Sentence denotes 2012)
T599 38544-38637 Sentence denotes Proliferation and maturational fate of neural progenitors and oligodendroglia • HIVSF162 (R5)
T600 38638-38740 Sentence denotes • HIVIIIB (X4) No Morphine • ↓ Proliferation of immature neural and OL progenitors with Tat + morphine
T601 38741-38792 Sentence denotes • ↓ NPC DNA synthesis with R5-tropic HIV + morphine
T602 38793-38913 Sentence denotes • ↑ NPC DNA synthesis with X4-tropic HIV + morphine Mouse, Tat tg; Mouse, Human, primary neural progenitors (Hahn et al.
T603 38914-38919 Sentence denotes 2012)
T604 38920-38947 Sentence denotes GABA function • HIVBaL (R5)
T605 38948-38975 Sentence denotes • gp120 (ADA, MN, and IIIB)
T606 38976-39038 Sentence denotes • Tat1–86 No Morphine • Tat or morphine ↓ KCC2 levels via CCR5
T607 39039-39168 Sentence denotes • ↑ KCC2 prevents Tat and R5 HIV, gp120, but not X4, gp120 neurotoxicity ± morphine Human, primary neurons, hNPCs (Barbour et al.
T608 39169-39174 Sentence denotes 2020)
T609 39175-39227 Sentence denotes Astroglial CCL5 and neuroprotection • gp120IIIB (X4)
T610 39228-39265 Sentence denotes • gp120BaL (R5) No • Morphine (10 μM)
T611 39266-39334 Sentence denotes • DAMGO • Morphine ↑ astroglial CCL5 blocking gp120BaL neurotoxicity
T612 39335-39486 Sentence denotes • Morphine (or CXCL12) does not block gp120IIIB neurotoxicity Rat, mixed neurons and glia; isolated neurons, astrocytes and microglia (Avdoshina et al.
T613 39487-39492 Sentence denotes 2010)
T614 39493-39586 Sentence denotes aassumed Clade B, unless noted otherwise, b statistical findings for some results are unclear
T615 39587-40497 Sentence denotes ARV, antiretroviral(s); BMVEC, brain vascular endothelial cells; [Ca2+]i intracellular calcium concentration; 8-CAC, 8-carboxamidocyclazocine; DAMGO, D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DCF, dihydro-dichlorofluorescein; DOR, δ-opioid receptor; DHE, dihydroethidium; DTG, dolutegravir; DPDPE, [D-Pen2,D-Pen5]enkephalin; FTC, emtricitabine; GABA, γ-aminobutyric acid; Iba1, ionized calcium-binding adapter molecule 1; JAM-1, junctional adhesion molecule-1; KCC2, K+-Cl− cotransporter 2; KOR, κ-opioid receptor; LTR, long terminal repeat; ΔΨm, mitochondrial inner membrane potential; MOR, μ-opioid receptor; [Na+]i, intracellular sodium concentration; nor-BNI, nor-binaltorphimine; NPCs, neural progenitor cells; OLs, oligodendroglia; ROS, reactive oxygen species; TEER, transendothelial electrical resistance; TFV, tenofovir; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; ZDV, zidovudine
T616 40498-40647 Sentence denotes For practicality, the table is limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes.
T617 40648-41055 Sentence denotes With deference toward the excellent studies we excluded: (1) on opioid and HIV effects on PBMCs, or on isolated lymphocytes and monocytes, not directly related to the central nervous system or BBB; (2) on HIV or opioid and ARV interactions in the peripheral nervous system; and (3) studies not directly examining opioid-HIV interactions (irrespective of whether a positive or negative interaction was found)
T618 41057-41106 Sentence denotes Opioid and HIV Interactive Pathology in Astroglia
T619 41107-41201 Sentence denotes Although the extent to which astroglia display productive infection is debated (Russell et al.
T620 41202-41217 Sentence denotes 2017; Ko et al.
T621 41218-41324 Sentence denotes 2019), there is nevertheless considerable evidence of proviral integration in the CNS of PWH (Gorry et al.
T622 41325-41347 Sentence denotes 2003; Churchill et al.
T623 41348-41395 Sentence denotes 2009), infectious animal models (Eugenin et al.
T624 41396-41459 Sentence denotes 2011), and/or cultured human fetal astrocytes (Tornatore et al.
T625 41460-41476 Sentence denotes 1994; Liu et al.
T626 41477-41492 Sentence denotes 2004; Do et al.
T627 41493-41516 Sentence denotes 2014; Narasipura et al.
T628 41517-41532 Sentence denotes 2014; Li et al.
T629 41533-41559 Sentence denotes 2015; Nath 2015; Li et al.
T630 41560-41566 Sentence denotes 2020).
T631 41567-41704 Sentence denotes Integrated HIV sequences have been identified in astrocytes in HIV-infected CNS tissue by laser capture microdissection (Churchill et al.
T632 41705-41711 Sentence denotes 2006).
T633 41712-41870 Sentence denotes Astroglia appear to infect via non-classical, CD4-independent mechanisms, that can have the appearance of virologic synapses, adding to the debate (Liu et al.
T634 41871-41886 Sentence denotes 2004; Do et al.
T635 41887-41902 Sentence denotes 2014; Li et al.
T636 41903-41936 Sentence denotes 2015; Nath 2015; Al-Harthi et al.
T637 41937-41952 Sentence denotes 2019; Li et al.
T638 41953-41959 Sentence denotes 2020).
T639 41960-42206 Sentence denotes Irrespective of whether they become infected, MOR-expressing, HIV or HIV protein-exposed astrocytes release greater amounts of inflammatory cytokines and dysfunction sufficient to harm bystander neurons upon treatment with opiates (El-Hage et al.
T640 42207-42230 Sentence denotes 2005, 2008b; Zou et al.
T641 42231-42251 Sentence denotes 2011; El-Hage et al.
T642 42252-42258 Sentence denotes 2014).
T643 42259-42415 Sentence denotes MOR-expressing subsets of glia, especially microglia and astroglia, are prominent in driving the interactive opioid and HIV neuropathogenesis (Hauser et al.
T644 42416-42461 Sentence denotes 2007, 2012; Hauser and Knapp 2014; Liu et al.
T645 42462-42484 Sentence denotes 2016a; Chilunda et al.
T646 42485-42504 Sentence denotes 2019; Murphy et al.
T647 42505-42511 Sentence denotes 2019).
T648 42512-42672 Sentence denotes When MOR is deleted from glia (astrocytes and microglia), morphine no longer increases the death of Tat-exposed striatal medium spiny neurons (MSNs) (Zou et al.
T649 42673-42679 Sentence denotes 2011).
T650 42680-42791 Sentence denotes Conversely, if MOR is deleted from MSNs, morphine exacerbates the neurotoxic effects of Tat in MSNs (Zou et al.
T651 42792-42798 Sentence denotes 2011).
T652 42799-42957 Sentence denotes The proinflammatory effects of Tat alone or in combination with morphine on glia are mediated through a Beclin-1-dependent autophagy pathway (Rodriguez et al.
T653 42958-42979 Sentence denotes 2017; Lapierre et al.
T654 42980-42986 Sentence denotes 2018).
T655 42987-43220 Sentence denotes Drugs with selective glial anti-inflammatory activity (i.e., ibudilast or AV411) attenuated the deleterious effects of HIV and opiate exposure, including HIV-1 replication, cytokine release, and neurotoxicity in vitro (El-Hage et al.
T656 43221-43227 Sentence denotes 2014).
T657 43228-43316 Sentence denotes Thus, the observed neuronal death is largely mediated by MOR-expressing glia (Zou et al.
T658 43317-43359 Sentence denotes 2011), including astroglia (El-Hage et al.
T659 43360-43410 Sentence denotes 2005, 2008b) and microglia (Turchan-Cholewo et al.
T660 43411-43431 Sentence denotes 2008; Bokhari et al.
T661 43432-43460 Sentence denotes 2009; Turchan-Cholewo et al.
T662 43461-43479 Sentence denotes 2009; Gupta et al.
T663 43480-43486 Sentence denotes 2010).
T664 43487-43622 Sentence denotes The direct contributions of astrocytes to opioid and HIV interactions have been discussed previously (Dutta and Roy 2012; Hauser et al.
T665 43623-43641 Sentence denotes 2012; Reddy et al.
T666 43642-43671 Sentence denotes 2012; Hauser and Knapp 2014).
T667 43672-43769 Sentence denotes Subsets of astroglia can express MOR, DOR and KOR (Stiene-Martin and Hauser 1991; Eriksson et al.
T668 43770-43790 Sentence denotes 1992; Ruzicka et al.
T669 43791-43811 Sentence denotes 1995; Gurwell et al.
T670 43812-43831 Sentence denotes 1996; Hauser et al.
T671 43832-43853 Sentence denotes 1996; Peterson et al.
T672 43854-43880 Sentence denotes 1998; Stiene-Martin et al.
T673 43881-43946 Sentence denotes 1998, 2001), as well as endogenous opioid peptides (Vilijn et al.
T674 43947-43967 Sentence denotes 1988; Shinoda et al.
T675 43968-43987 Sentence denotes 1989; Spruce et al.
T676 43988-44007 Sentence denotes 1990; Hauser et al.
T677 44008-44024 Sentence denotes 1990; Low et al.
T678 44025-44031 Sentence denotes 1992).
T679 44032-44215 Sentence denotes It appears that the ‘early’ events triggering the release of proinflammatory cytokines (i.e., TNF-α and IL-1β) from astroglia can be mediated by HIV Tat exposure alone (El-Hage et al.
T680 44216-44239 Sentence denotes 2005, 2006a, b, 2008a).
T681 44240-44521 Sentence denotes Opioids enhance HIV-1-induced inflammation later during the inflammatory cascade by exacerbating the sustained release of CCL5 from astrocytes, which subsequently triggers the release of CCL2 thereby enhancing the recruitment and activation of macrophages/microglia (El-Hage et al.
T682 44522-44538 Sentence denotes 2008a) (Fig. 1).
T683 44539-44695 Sentence denotes This is caused by the morphine-dependent exacerbation of Tat-induced increases in intracellular calcium concentration ([Ca2+]i) in astroglia (El-Hage et al.
T684 44696-44859 Sentence denotes 2005), which accelerates the trafficking of NF-κB p65 (RelA) subunits to the nucleus and sustained CCL2, CCL5, and IL-6 transcription in astrocytes (El-Hage et al.
T685 44860-44867 Sentence denotes 2008b).
T686 44868-45071 Sentence denotes Fig. 1 Opioids exacerbate HIV-1-induced CNS inflammation, in part, by augmenting CCL5-dependent increases in CCL2—key sites of opioid-HIV convergent interactions in glial inflammatory signaling cascades.
T687 45072-45346 Sentence denotes Subpopulations of striatal glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in wildtype mice normally express CCR2 immunoreactivity (a-b; arrows), CCL2 (c; arrow), or μ-opioid receptor (MOR) (d; arrows) immunoreactivity (scale bars a-b = 25 μm; c-d = 15 μm).
T688 45347-45627 Sentence denotes CCR2 deletion (−/−) significantly reduces HIV-1 Tat ± morphine-induced increases in GFAP+ astroglia (e) and F4/80+ macrophages/microglia (f) compared to wild type (+/+) mice at sites near (300 ± 100 μm) the site of Tat injection (*p < 0.05 vs. wild type mice) (see, El-Hage et al.
T689 45628-45635 Sentence denotes 2006a).
T690 45636-46184 Sentence denotes In wild-type mice, Tat ± morphine administration markedly increases the proportion of CCL2 immunoreactive astrocytes (g) or macrophages/microglia (h) [*p < 0.05 vs. other groups in wild-type or CCL5(−/−) mice; bp < 0.05 vs. vehicle- or Tat plus morphine-treated wild-type mice; #p < 0.05 vs. equivalent treatment in wild-type mice], while in CCL5 null mice, significant increases in CCL2 immunoreactivity were only seen in macrophages/microglia co-exposed to Tat and morphine (§p < 0.05 vs. vehicle injected CCL5 knockout mice) (see, El-Hage et al.
T691 46185-46192 Sentence denotes 2008a).
T692 46193-46365 Sentence denotes CCL5 expression in striatal GFAP-immunoreactive astrocytes (arrows) increases following Tat injections (i, j) compared to wild-type control mice (not shown) (El-Hage et al.
T693 46366-46373 Sentence denotes 2008a).
T694 46374-46626 Sentence denotes Opioids exacerbate HIV-1-induced CNS inflammation, in part, by increasing CCL5 and augmenting CCR5-dependent increases in CCL2 production by astrocytes resulting in the activation and recruitment of microglia/macrophages and spiraling inflammation (k).
T695 46627-46732 Sentence denotes Additional factors likely mediate the proinflammatory cascade, but these are less well substantiated (?).
T696 46733-47148 Sentence denotes Moreover, autocrine and reciprocal paracrine (astroglial ↔ macrophage/microglial) intercellular, feedback amplification mechanisms from macrophages/microglia are likely to be operative (dashed red arrow) (also see, Kang and Hebert 2011) and occur elsewhere within the cascade (not shown); effects of HIV-1 Tat/HIV, red arrows; sites of opioid convergence, blue arrows; pro-BDNF:mature BDNF (mBDNF) ratio (Kim et al.
T697 47149-47302 Sentence denotes 2018). (a-f) Modified and reprinted with permission from El-Hage et al. (2006a). (g-k) Modified and reprinted with permission from El-Hage et al. (2008a)
T698 47304-47353 Sentence denotes Opioid and HIV Interactive Pathology in Microglia
T699 47354-47465 Sentence denotes Unlike in astrocytes, opiate and HIV interactions in microglia tend to be self-limiting (Turchan-Cholewo et al.
T700 47466-47472 Sentence denotes 2009).
T701 47473-47657 Sentence denotes Opiates initially trigger large increases in the production of proinflammatory cytokines (Hauser, unpublished), reactive oxygen (ROS) and nitrogen (RNS) species (Turchan-Cholewo et al.
T702 47658-47707 Sentence denotes 2009), and the release of glutamate (Gupta et al.
T703 47708-47789 Sentence denotes 2010) and ATP (Sorrell and Hauser 2014) extracellularly in Tat-exposed microglia.
T704 47790-47911 Sentence denotes The release of glutamate is mediated by the catalytic subunit of the cystine-glutamate antiporter xc− (xCT) (Gupta et al.
T705 47912-47918 Sentence denotes 2010).
T706 47919-48158 Sentence denotes Interestingly, following acute increases in the release of cytokines (e.g., TNF-α; unpublished), morphine no longer increases Tat-induced cytokine levels at 24 h; instead, their levels are reduced by opiate-dependent proteasome inhibition.
T707 48159-48388 Sentence denotes The proteasome inhibitor, MG115, mimics the effects of morphine in decreasing proteasome activity at 24 h and blocks TNFα, IL-6, and CCL2 release from microglia, but does not increase ROS or RNS production (Turchan-Cholewo et al.
T708 48389-48395 Sentence denotes 2009).
T709 48396-48562 Sentence denotes The ubiquitin proteasome system (UPS) is typically viewed as contributing to opiate tolerance and physical dependence by modulating MOR downregulation (Massaly et al.
T710 48563-48582 Sentence denotes 2014; Caputi et al.
T711 48583-48636 Sentence denotes 2019), rather than MOR activity constraining the UPS.
T712 48637-48984 Sentence denotes Thus, while HIV-exposed, MOR-expressing microglia show a burst of ROS and proinflammatory cytokine production in response to morphine, the cytokine release collapses within 24 h seemingly because sustained opiate exposure inhibits the UPS thereby preventing degradation of the IκB subunit and nuclear translocation of NF-κB (Turchan-Cholewo et al.
T713 48985-48991 Sentence denotes 2009).
T714 48992-49197 Sentence denotes While neither astroglia nor microglia alone mimic the full inflammatory profile seen with opiates and HIV in the CNS; in combination, the neuroimmune signature more accurately mimics that seen in neuroHIV.
T715 49198-49398 Sentence denotes Accordingly, we have proposed that opioids promote positive feedback through separate actions in astroglia and microglia in neuroHIV—resulting in spiraling inflammation and cytotoxicity (Hauser et al.
T716 49399-49411 Sentence denotes 2005, 2007).
T717 49413-49460 Sentence denotes Opioid and HIV Interactive Pathology in Neurons
T718 49461-49765 Sentence denotes Besides accentuating HIV-induced neurotoxicity via glial-mediated mechanisms, morphine appears to converge with HIV Tat to dysregulate ion homeostasis and dendritic injury through potential direct actions on neurons, even though some contributions of glia cannot be excluded in this study (Fitting et al.
T719 49766-49773 Sentence denotes 2014a).
T720 49774-50095 Sentence denotes Combined morphine and Tat exposure accelerates the formation of Tat-induced focal dendritic varicosities/swelling via a MOR-related mechanism that was caused by focal increases in Na+ influx and [Ca2+]i, an overload of Na+/K+-ATPase, ATP depletion, and a collapse in mitochondrial inner membrane potential (Fitting et al.
T721 50096-50103 Sentence denotes 2014a).
T722 50104-50322 Sentence denotes Importantly, morphine’s additive effects were mediated via a MOR-related mechanism, as the exacerbating effects of morphine were absent in neurons from MOR knockout mice, thus excluding TLR4 involvement (Fitting et al.
T723 50323-50330 Sentence denotes 2014a).
T724 50331-50487 Sentence denotes Further, morphine exacerbated Tat-dependent focal losses in ion homeostasis by mobilizing [Ca2+]i through ryanodine-2 (RyR2)-sensitive sites (Fitting et al.
T725 50488-50504 Sentence denotes 2014a) (Fig. 2).
T726 50505-50612 Sentence denotes Although morphine typically acts via MOR in an inhibitory manner by activating Gi/o-proteins (Sharma et al.
T727 50613-50632 Sentence denotes 1977; Moises et al.
T728 50633-50746 Sentence denotes 1994; Al-Hasani and Bruchas 2011), MOR-dependent stimulation of PI3-kinase and Ca2+ mobilization (Leopoldt et al.
T729 50747-50807 Sentence denotes 1998) in neurons via the Gβγ protein subunit (Mathews et al.
T730 50808-50850 Sentence denotes 2008) is presumed operative here (Fig. 2).
T731 50851-51148 Sentence denotes Fig. 2 Morphine exacerbates the excitotoxic effects of HIV Tat by mobilizing Ca2+ from ryanodine (RyR)-sensitive internal stores. (a) Tat-induced increases in [Ca2+]i were not attenuated by ryanodine, whereas ryanodine and pyruvate attenuate combined Tat and morphine-induced increases in [Ca2+]i.
T732 51149-51501 Sentence denotes Nimodipine (L-type Ca2+ channel blocker) and dantrolene did not show any effects. (b) Average [Ca2+]i over 10 min indicated ryanodine significantly blocked combined Tat and morphine-induced increases in [Ca2+]i, whereas no effects were noted for nimodipine, dantrolene, or pyruvate. *p < 0.05 vs. control, #p < 0.05 vs. Tat 50 nM, §p < 0.05 vs. TM, TM:
T733 51502-51630 Sentence denotes Tat 50 nM + Morphine 500 nM. (c) Summary of HIV-1 Tat and morphine interactive neuronal injury in striatal medium spiny neurons.
T734 51631-52076 Sentence denotes Combined Tat and morphine promotes structural and functional defects in dendrites via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), N-methyl-D-aspartic acid receptors (NMDAR), and MOR, causing influxes of Na+ and/or Ca2+, compensatory increases in Na+/K+-dependent ATPase activity, and a rapid loss in ATP mobilization with an inability to extrude excess Na+ via Na+/K+-ATPase caused by mitochondrial hyperpolarization.
T735 52077-52508 Sentence denotes Dysregulation of [Ca2+]i homeostasis by combined Tat and morphine appears to be mediated downstream of [Na+]i at the level of calcium mobilization, which in turn appears to be regulated via ryanodine (RyR)-sensitive sites, and enhanced by morphine exposure likely via MOR-dependent stimulation of PI3-kinase and Ca2+ mobilization via the Gβγ protein subunit. (a-b) Modified and reprinted with permission from Fitting et al. (2014a)
T736 52509-52561 Sentence denotes Glial-derived neuronal injury is not unidirectional.
T737 52562-52760 Sentence denotes Neuronal damage-associated molecular patterns (DAMPs) and dysfunction can trigger both infected and uninfected glia to become reactive, resulting in further neuronal damage and escalating pathology.
T738 52761-52852 Sentence denotes Neuronal injury can reactivate HIV in latently infected microglia (Alvarez-Carbonell et al.
T739 52853-52859 Sentence denotes 2019).
T740 52860-53318 Sentence denotes While the events underlying the disruption of neuronal-microglial activation that trigger the emergence of latent HIV are unclear, the induction of HIV expression appears to involve the production of DAMPs by injured neurons and can be turned “on”, e.g., by methamphetamine-induced sigma-1 (σ1) receptor activation, TNF-α and IL-1β, and TLR3 activation can be turned “off” by CX3CL1/fractalkine or glucocorticoid receptor activation (Alvarez-Carbonell et al.
T741 53319-53331 Sentence denotes 2017, 2019).
T742 53333-53400 Sentence denotes Neural Systems Selectively Disrupted by Opiate and HIV Interactions
T743 53402-53448 Sentence denotes Blood-Brain Barrier and the Neurovascular Unit
T744 53449-53624 Sentence denotes Despite growing evidence on how opiates and HIV interact to impact the neuropathology of HIV, little is known about their interactive effects on the blood-brain barrier (BBB).
T745 53625-53787 Sentence denotes BBB integrity and function are critical for maintaining CNS homeostasis, and mediating neuroimmune interactions with the periphery and drug delivery into the CNS.
T746 53788-53898 Sentence denotes HIV and many individual HIV proteins can breakdown the BBB disrupting tight junction proteins (Dallasta et al.
T747 53899-53917 Sentence denotes 1999; Boven et al.
T748 53918-53937 Sentence denotes 2000; Andras et al.
T749 53938-53958 Sentence denotes 2003; Mahajan et al.
T750 53959-53980 Sentence denotes 2008; Banerjee et al.
T751 53981-54000 Sentence denotes 2010; Gandhi et al.
T752 54001-54016 Sentence denotes 2010; Xu et al.
T753 54017-54035 Sentence denotes 2012; Patel et al.
T754 54036-54161 Sentence denotes 2017) and decreasing transendothelial electrical resistance (TEER) (an in vitro measure of barrier integrity) (Mahajan et al.
T755 54162-54181 Sentence denotes 2008; Gandhi et al.
T756 54182-54223 Sentence denotes 2010; Mishra and Singh 2014; Patel et al.
T757 54224-54351 Sentence denotes 2017), with resultant paracellular “leakage” of compounds/current between compromised barrier endothelial cells (Mahajan et al.
T758 54352-54371 Sentence denotes 2008; Gandhi et al.
T759 54372-54388 Sentence denotes 2010; Wen et al.
T760 54389-54408 Sentence denotes 2011; McLane et al.
T761 54409-54430 Sentence denotes 2014; Leibrand et al.
T762 54431-54443 Sentence denotes 2017, 2019).
T763 54444-54579 Sentence denotes Although opioids can also impair the BBB through alterations in tight junction proteins and/or increased paracellular flux (Baba et al.
T764 54580-54600 Sentence denotes 1988; Mahajan et al.
T765 54601-54617 Sentence denotes 2008; Wen et al.
T766 54618-54639 Sentence denotes 2011; Leibrand et al.
T767 54640-54800 Sentence denotes 2019), others have found that it is morphine withdrawal, not the continued exposure to morphine, that most greatly disrupts BBB integrity (Sharma and Ali 2006).
T768 54801-54960 Sentence denotes In addition to perturbing paracellular dynamics, morphine may also alter the expression and/or function of drug efflux proteins, such as P-glycoprotein (P-gp).
T769 54961-55076 Sentence denotes Sub-chronic and chronic morphine exposure is reported to increase P-gp expression and/or function (Aquilante et al.
T770 55077-55097 Sentence denotes 2000; Mahajan et al.
T771 55098-55117 Sentence denotes 2008; Yousif et al.
T772 55118-55139 Sentence denotes 2008; Leibrand et al.
T773 55140-55146 Sentence denotes 2019).
T774 55147-55244 Sentence denotes Alternatively, other investigators report no changes in P-gp with chronic exposure (Chaves et al.
T775 55245-55316 Sentence denotes 2016), while some see increases upon morphine withdrawal (Yousif et al.
T776 55317-55336 Sentence denotes 2012; Chaves et al.
T777 55337-55343 Sentence denotes 2016).
T778 55344-55481 Sentence denotes Alterations in drug transport proteins would impact the central accumulation and efficacy of therapeutic drugs that are their substrates.
T779 55482-55824 Sentence denotes Using a primary human brain microvascular endothelial cell (BMEC) and astrocyte co-culture model, Mahajan et al. (2008) were among the first to demonstrate that co-exposure to morphine and HIV-1 Tat resulted in greater increases in TNF-α and IL-8 levels and decreases in barrier tightness (measured by TEER) than either morphine or Tat alone.
T780 55825-56065 Sentence denotes Morphine and Tat co-exposure also additively increased JAM-2, while zonula occludens-1 (ZO-1) levels were decreased by morphine or by Tat individually, and occludin protein levels were decreased by morphine alone but not Tat (Mahajan et al.
T781 56066-56072 Sentence denotes 2008).
T782 56073-56234 Sentence denotes Using the inducible Tat transgenic mouse model, Leibrand et al. (2019), also demonstrated that HIV-1 Tat and morphine act independently to disrupt BBB integrity.
T783 56235-56408 Sentence denotes In these studies, morphine, and to a lesser extent Tat, exposure increased the leakage of fluorescently labeled dextrans from the circulation into the brain (Leibrand et al.
T784 56409-56430 Sentence denotes 2017, 2019) (Fig. 3).
T785 56431-56548 Sentence denotes Morphine exposure decreased the penetration of select ARVs in the brain, in a region-specific manner (Leibrand et al.
T786 56549-56564 Sentence denotes 2019) (Fig. 3).
T787 56565-56768 Sentence denotes Morphine exposure also resulted in increased expression and function of the drug efflux transport protein, P-gp, suggesting a mechanism by which morphine decreased the ARV concentrations (Leibrand et al.
T788 56769-56775 Sentence denotes 2019).
T789 56776-56922 Sentence denotes This finding suggests that morphine exposure could impact the efficient delivery of any therapeutic drug that is a substrate of P-gp into the CNS.
T790 56923-57054 Sentence denotes Future research should also investigate morphine’s impact on other drug transport proteins important for ARV delivery to the brain.
T791 57055-57156 Sentence denotes Fig. 3 Effects of HIV-1 Tat and morphine on BBB leakiness and on antiretroviral brain concentrations.
T792 57157-57447 Sentence denotes After 14 days of Tat induction, there was a significant increase in the 10 kDa (Cascade Blue®) tracer leakage into the brain in Tat + placebo as compared to Tat − placebo mice (*p < 0.05) and in Tat − mouse brains upon exposure to morphine as compared to Tat − placebo mice (*p < 0.05) (a).
T793 57448-57796 Sentence denotes There was a significant main effect of morphine, resulting in reduced integrity of the BBB and increased leakage of the higher molecular weight (40 kDa and 70 kDa) tracers in morphine-exposed groups as compared to the those groups (Tat + and Tat − together) not exposed to morphine (placebo) (#p < 0.05; significant main effect of morphine) (b, c).
T794 57797-57956 Sentence denotes Data represent the fold change in mean fluorescence intensity ± SEM; n = 8 Tat−/placebo, n = 6 Tat+/placebo, n = 9 Tat−/morphine, and n = 7 Tat+/morphine mice.
T795 57957-58132 Sentence denotes Additionally, morphine exposure increased horseradish peroxidase (HRP) extravasation from the vasculature into the perivascular space and/or parenchyma in the striatum (d, e).
T796 58133-58370 Sentence denotes HRP antigenicity was detected by indirect immunofluorescence (red) in tissue sections counterstained with Hoechst 33342 (blue) to reveal cell nuclei and visualized by differential interference contrast (DIC)-enhanced confocal microscopy.
T797 58371-58532 Sentence denotes HRP extravasation into the striatal perivascular space/parenchyma was especially prevalent in morphine-exposed mice (arrowheads; left-hand panels in e versus d).
T798 58533-58803 Sentence denotes The dotted lines (············) indicate the approximate edge of the capillaries/post-capillary venules; while intermittent dotted lines (· · · · · · ·) indicate the approximate edge of a partly sectioned blood vessel that appears partially outside the plane of section.
T799 58804-58871 Sentence denotes The asterisks (*) indicate white matter tracts within the striatum.
T800 58872-58923 Sentence denotes Representative samples from ≥ n = 4 mice per group.
T801 58924-58962 Sentence denotes All images are the same magnification.
T802 58963-58981 Sentence denotes Scale bar = 10 μm.
T803 58982-59039 Sentence denotes Antiretroviral tissue-to-plasma ratios in striatum (f–g).
T804 59040-59258 Sentence denotes Irrespective of Tat exposure, morphine significantly reduced the levels of dolutegravir (f) and abacavir (g), but not lamivudine (h), within the striatum, as compared to placebo. (* p < 0.05; main effect for morphine).
T805 59259-59484 Sentence denotes Data represent the tissue-to-plasma ratios ± SEM sampled from n = 9 Tat−/placebo, n = 9 Tat+/placebo, n = 6 Tat−/morphine, and n = 8 Tat+/morphine mice. (a–h) Modified and reprinted with permission from Leibrand et al. (2019)
T806 59485-59647 Sentence denotes HIV, HIV-1 viral proteins, and opiate-induced barrier dysfunction is associated with increased infiltration of monocyte-derived macrophages (MDMs) into the brain.
T807 59648-59794 Sentence denotes Enhanced influx of peripheral (infected) macrophages into the brain can serve to replenish viral reservoirs and further promote neuroinflammation.
T808 59795-59933 Sentence denotes Several studies have examined the individual impact of HIV, Tat, or morphine on monocyte adhesion or migration into the CNS (Nottet et al.
T809 59934-59949 Sentence denotes 1996; Wu et al.
T810 59950-59976 Sentence denotes 2000; Fischer-Smith et al.
T811 59977-59995 Sentence denotes 2001; Pello et al.
T812 59996-60017 Sentence denotes 2006; Williams et al.
T813 60018-60045 Sentence denotes 2013a, 2014; Strazza et al.
T814 60046-60067 Sentence denotes 2016; Leibrand et al.
T815 60068-60089 Sentence denotes 2017; Chilunda et al.
T816 60090-60096 Sentence denotes 2019).
T817 60097-60178 Sentence denotes However, fewer studies have examined the combined effects of HIV/Tat and opiates.
T818 60179-60337 Sentence denotes Co-exposure of HIV-1 Tat and morphine on astrocytes increases the production of chemoattractants, primarily CCL2 and CCL5, and increases microglial migration.
T819 60338-60398 Sentence denotes These effects were inhibited by MOR blockade (El-Hage et al.
T820 60399-60406 Sentence denotes 2006b).
T821 60407-60561 Sentence denotes Co-exposure of Tat and morphine or buprenorphine to a BBB model increases monocyte transmigration in response to CCL5 and other chemokines (Mahajan et al.
T822 60562-60595 Sentence denotes 2008; Jaureguiberry-Bravo et. al.
T823 60596-60602 Sentence denotes 2016).
T824 60603-60776 Sentence denotes In S. pneumoniae-infected mice, morphine and/or Tat exposure significantly enhances immune cell trafficking into the brain via actions at TLR2 and TLR4 (Dutta and Roy 2015).
T825 60777-60873 Sentence denotes Taken together, BBB damage from HIV and/or opiates can disrupt the homeostasis within the brain.
T826 60874-61201 Sentence denotes Breakdown of paracellular processes, through decreases in tight junction proteins and increased cellular adhesion proteins, increased leakage of circulating molecules into the brain and increased monocyte/MDM adhesion and transmigration into the brain, which if infected, can serve to replenish viral reservoirs within the CNS.
T827 61202-61331 Sentence denotes Furthermore, alterations in drug transport proteins within the brain can decrease ARV efficacy by decreasing drug concentrations.
T828 61332-61438 Sentence denotes Collectively, these changes serve to maintain HIV infection within the brain (see Fig. 4; Tables 1 and 2).
T829 61439-61545 Sentence denotes Fig. 4 Schematic representation of the blood-brain barrier and other components of the neurovascular unit.
T830 61546-61757 Sentence denotes Under normal conditions (represented above the dotted line), tight junctions are intact which restricts the leakage of paracellular, typically small hydrophilic, compounds, across the barrier and into the brain.
T831 61758-61957 Sentence denotes Additionally, there is a basal expression of efflux transporters, such as P-glycoprotein (P-gp), which effluxes substrates out of the brain, serving to restrict overall accumulation within the brain.
T832 61958-62152 Sentence denotes In the setting of HIV and opiate exposure (represented below the dotted line), there is a breakdown of the tight junction proteins and increased leakage of paracellular compounds into the brain.
T833 62153-62474 Sentence denotes Additionally, opiate exposure increases efflux transporter expression, including P-gp and potentially breast cancer resistance protein (Bcrp), thereby restricting overall brain penetration of drugs (like many antiretroviral drugs) which are substrates for these transporters and in response to HIV and/or opioid exposure.
T834 62476-62515 Sentence denotes White Matter/Oligodendroglial Pathology
T835 62516-62567 Sentence denotes HIV can cause white matter damage (Gosztonyi et al.
T836 62568-62589 Sentence denotes 1994; Langford et al.
T837 62590-62607 Sentence denotes 2002; Xuan et al.
T838 62608-62662 Sentence denotes 2013) even with less severe forms of HAND (Chen et al.
T839 62663-62681 Sentence denotes 2009; Leite et al.
T840 62682-62701 Sentence denotes 2013; Correa et al.
T841 62702-62708 Sentence denotes 2015).
T842 62709-62819 Sentence denotes Diffusion tensor magnetic resonance imaging (DTI) demonstrates white matter damage early in HAND (Ragin et al.
T843 62820-62845 Sentence denotes 2004; Stubbe-Drger et al.
T844 62846-62864 Sentence denotes 2012; Leite et al.
T845 62865-62884 Sentence denotes 2013; Correa et al.
T846 62885-62891 Sentence denotes 2015).
T847 62892-63000 Sentence denotes White matter deficits are associated with cognitive impairment, including shortfalls in memory (Ragin et al.
T848 63001-63041 Sentence denotes 2005), executive function (Correa et al.
T849 63042-63071 Sentence denotes 2015), motor speed (Wu et al.
T850 63072-63097 Sentence denotes 2006; Stubbe-Drger et al.
T851 63098-63158 Sentence denotes 2012), and perhaps depression (Schmaal and van Velzen 2019).
T852 63159-63261 Sentence denotes Preclinical studies in simian immunodeficiency virus- (SIV-) infected rhesus macaques (Marcario et al.
T853 63262-63313 Sentence denotes 2008) and HIV-infected humanized mice (Boska et al.
T854 63314-63350 Sentence denotes 2014) support the clinical findings.
T855 63351-63443 Sentence denotes Injury to oligodendrocytes (OLs) can occur very early in the disease (see review, Liu et al.
T856 63444-63451 Sentence denotes 2016b).
T857 63452-63563 Sentence denotes Viral proteins, including Tat, gp120, and Nef, have been implicated in OL injury in vitro (Kimura-Kuroda et al.
T858 63564-63585 Sentence denotes 1994; Bernardo et al.
T859 63586-63604 Sentence denotes 1997; Radja et al.
T860 63605-63626 Sentence denotes 2003; Nukuzuma et al.
T861 63627-63643 Sentence denotes 2012; Zou et al.
T862 63644-63693 Sentence denotes 2015), and in animal models in vivo (Radja et al.
T863 63694-63713 Sentence denotes 2003; Hauser et al.
T864 63714-63730 Sentence denotes 2009; Zou et al.
T865 63731-63737 Sentence denotes 2015).
T866 63738-63828 Sentence denotes Importantly, Tat has been detected in OLs in the brains of AIDS patients (Del Valle et al.
T867 63829-63835 Sentence denotes 2000).
T868 63836-63900 Sentence denotes HIV likely damages OLs through both direct and indirect actions.
T869 63901-63976 Sentence denotes OLs lack CD4, and reports of OL infection by HIV are variable (Esiri et al.
T870 63977-63998 Sentence denotes 1991; Albright et al.
T871 63999-64025 Sentence denotes 1996; Wohlschlaeger et al.
T872 64026-64134 Sentence denotes 2009); thus, HIV infection of OLs is unlikely a major avenue of OL or white matter damage (discussed below).
T873 64135-64322 Sentence denotes Alternatively, bystander damage to OLs through the production of “virotoxins” and “cellular toxins” (Nath 1999) by infected neighboring cells is more likely to be operative (Hauser et al.
T874 64323-64339 Sentence denotes 2009; Zou et al.
T875 64340-64359 Sentence denotes 2015; Jensen et al.
T876 64360-64376 Sentence denotes 2019; Zou et al.
T877 64377-64383 Sentence denotes 2019).
T878 64384-64438 Sentence denotes ARVs also contribute to OL cytotoxicity (Jensen et al.
T879 64439-64457 Sentence denotes 2015; Festa et al.
T880 64458-64477 Sentence denotes 2019; Jensen et al.
T881 64478-64484 Sentence denotes 2019).
T882 64485-64676 Sentence denotes HIV-1 Tat directly induces damage in isolated OLs through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-D-aspartic acid (NMDA) receptor-dependent mechanisms (Zou et al.
T883 64677-64746 Sentence denotes 2015) and is also associated with abnormal Kv1.3 activity (Liu et al.
T884 64747-64753 Sentence denotes 2017).
T885 64754-64850 Sentence denotes Immature OLs are preferentially targeted by Tat compared to differentiated OLs (Khurdayan et al.
T886 64851-64868 Sentence denotes 2004; Hahn et al.
T887 64869-64885 Sentence denotes 2012; Zou et al.
T888 64886-64898 Sentence denotes 2015, 2019).
T889 64899-65147 Sentence denotes While the reasons why immature OLs are more susceptible to Tat are unclear, unlike mature OLs, Tat preferentially upregulates GSK-3β signaling in undifferentiated OLs by inhibiting Ca2+/calmodulin-dependent protein kinase II β (CaMKIIβ) (Zou et al.
T890 65148-65154 Sentence denotes 2019).
T891 65155-65319 Sentence denotes Opioid abuse by itself can result in demyelination, leukoencephalopathy, and lesions in white matter (Offiah and Hall 2008; Eran and Barak 2009; Morales Odia et al.
T892 65320-65337 Sentence denotes 2010; Bora et al.
T893 65338-65353 Sentence denotes 2012; Li et al.
T894 65354-65460 Sentence denotes 2013), and the degree of myelin disruption correlates with the duration of opiate dependence (Ivers et al.
T895 65461-65467 Sentence denotes 2018).
T896 65468-65685 Sentence denotes Chronic oxycodone exposure in rats causes some axonopathies and reduces the size of axonal fascicles, decreases myelin basic protein levels, and causes the accumulation of amyloid-β precursor protein (APP) (Fan et al.
T897 65686-65692 Sentence denotes 2018).
T898 65693-65848 Sentence denotes Most preclinical studies have examined the effects of opioids and opioid receptor blockade on OL maturation and/or the timing of myelination (Hauser et al.
T899 65849-65867 Sentence denotes 1993; Knapp et al.
T900 65868-65894 Sentence denotes 1998; Stiene-Martin et al.
T901 65895-65915 Sentence denotes 2001; Sanchez et al.
T902 65916-65934 Sentence denotes 2008; Knapp et al.
T903 65935-65962 Sentence denotes 2009; Vestal-Laborde et al.
T904 65963-65969 Sentence denotes 2014).
T905 65970-66048 Sentence denotes OLs can transiently express MORs and other opioid receptor types (Knapp et al.
T906 66049-66073 Sentence denotes 1998; Tryoen-Toth et al.
T907 66074-66092 Sentence denotes 2000; Knapp et al.
T908 66093-66119 Sentence denotes 2001; Stiene-Martin et al.
T909 66120-66126 Sentence denotes 2001).
T910 66127-66254 Sentence denotes Selective MOR and possibly KOR activation can directly modulate the growth of OLs in vitro (Knapp and Hauser 1996; Knapp et al.
T911 66255-66267 Sentence denotes 1998, 2001).
T912 66268-66387 Sentence denotes Despite long-standing evidence of white matter damage early during the infection even in asymptomatic PWH (Price et al.
T913 66388-66405 Sentence denotes 1988; Gray et al.
T914 66406-66423 Sentence denotes 1996; Chen et al.
T915 66424-66449 Sentence denotes 2009; Stubbe-Drger et al.
T916 66450-66469 Sentence denotes 2012; Jensen et al.
T917 66470-66575 Sentence denotes 2019), few studies have examined how opiate exposure affects OLs and myelin in neuroHIV (Tables 1 and 2).
T918 66576-66721 Sentence denotes Increased demyelination is reported in SIV-infected rhesus macaques chronically treated with morphine (4× daily, up to 59 weeks) (Marcario et al.
T919 66722-66728 Sentence denotes 2008).
T920 66729-66901 Sentence denotes Specifically, morphine-treated SIV macaques developed more subtle, focal, dysmyelinating lesions, with accumulations of macrophages in areas of myelin loss (Marcario et al.
T921 66902-66957 Sentence denotes 2008), as well as accompanying gliosis (Marcario et al.
T922 66958-66983 Sentence denotes 2008; Rivera-Amill et al.
T923 66984-67005 Sentence denotes 2010a; Bokhari et al.
T924 67006-67012 Sentence denotes 2011).
T925 67013-67232 Sentence denotes Morphine exposure increased degeneration of OLs in Tat+ mice, which was accompanied by elevations in caspase-3 activation and TUNEL reactivity in OLs and reversible by naloxone or naltrexone, respectively (Hauser et al.
T926 67233-67239 Sentence denotes 2009).
T927 67240-67303 Sentence denotes Although OLs can express MOR both in vivo (Stiene-Martin et al.
T928 67304-67337 Sentence denotes 2001) and in vitro (Hauser et al.
T929 67338-67441 Sentence denotes 2009), it remains unclear the extent to which MOR activation in OLs directly mediates HIV pathogenesis.
T930 67443-67504 Sentence denotes Neural Progenitors as an HIV Reservoir and Target for Opioids
T931 67505-67579 Sentence denotes Even though neural progenitors (Krathwohl and Kaiser 2004; Lawrence et al.
T932 67580-67605 Sentence denotes 2004; Rothenaigner et al.
T933 67606-67627 Sentence denotes 2007; Schwartz et al.
T934 67628-67649 Sentence denotes 2007; Balinang et al.
T935 67650-67693 Sentence denotes 2017), neuroblast cell lines (Ensoli et al.
T936 67694-67719 Sentence denotes 1994; Rothenaigner et al.
T937 67720-67767 Sentence denotes 2007), and/or immature astroglia (Atwood et al.
T938 67768-67790 Sentence denotes 1993; Tornatore et al.
T939 67791-67809 Sentence denotes 1994; Barat et al.
T940 67810-67893 Sentence denotes 2018) can harbor HIV infection (reviewed by Hauser and Knapp 2014; Putatunda et al.
T941 67894-68012 Sentence denotes 2019), the degree to which they are a source of active infection or serve as a latent viral reservoir (Blankson et al.
T942 68013-68032 Sentence denotes 2002; Bruner et al.
T943 68033-68121 Sentence denotes 2019) by retaining intact proviral DNA within incipient macroglial progeny is uncertain.
T944 68122-68198 Sentence denotes In fact, spurious reports of HIV-infected adult neurons (Torres-Munoz et al.
T945 68199-68224 Sentence denotes 2001; Canto-Nogues et al.
T946 68225-68382 Sentence denotes 2005) may result from the retention of proviral genes that integrated into pluripotent neural progenitors or neuroblasts at earlier stages during maturation.
T947 68383-68502 Sentence denotes Importantly, prolonged exposure to opioids can increase the production of HIV in human neural progenitor cells (hNPCs).
T948 68503-68668 Sentence denotes Exposure of R5-tropic HIVBaL-infected hNPCs to morphine continuously for 21 d increased viral production compared to HIVBaL infection alone in vitro (Balinang et al.
T949 68669-68675 Sentence denotes 2017).
T950 68676-68783 Sentence denotes Besides being able to infect hNPCs, HIV may also affect their maturation and the fate of neural stem cells.
T951 68784-68848 Sentence denotes That HIV or gp120 can inhibit adult neurogenesis (Okamoto et al.
T952 68849-68865 Sentence denotes 2007; Lee et al.
T953 68866-68888 Sentence denotes 2013; Putatunda et al.
T954 68889-68973 Sentence denotes 2018) has been the topic of past reviews (Schwartz and Major 2006; Venkatesan et al.
T955 68974-68991 Sentence denotes 2007; Peng et al.
T956 68992-69068 Sentence denotes 2008, 2011; Ferrell and Giunta 2014; Hauser and Knapp 2014; Putatunda et al.
T957 69069-69075 Sentence denotes 2019).
T958 69076-69283 Sentence denotes How HIV inhibits the self-renewal, tripotential differentiation, and survival of neural progenitors/stem cells or the genesis of adult neurons in the subgranular zone (SGZ) of the dentate gyrus is uncertain.
T959 69284-69461 Sentence denotes HIV and gp120 [via actions at the same chemokine receptor(s) (Tran and Miller 2005; Li and Ransohoff 2008)] are proposed to modulate the adult neurogenesis via Notch (Fan et al.
T960 69462-69587 Sentence denotes 2016), by obstructing a cell cycle checkpoint via the activation MAPK-activated protein kinase 2 and Cdc25B/C (Okamoto et al.
T961 69588-69665 Sentence denotes 2007), or through signaling by platelet-derived growth factor BB (Chao et al.
T962 69666-69691 Sentence denotes 2014) or BDNF (Lee et al.
T963 69692-69698 Sentence denotes 2013).
T964 69699-69988 Sentence denotes The extent that HIV regulates the genesis of neural progenitors within the subventricular zone of the developing CNS through similar mechanisms as in the adult SGZ of the dentate gyrus is uncertain—even though HIV disrupts the generation of neurons and glia during maturation or in adults.
T965 69989-70158 Sentence denotes For example, MAPK/ERK1/2 enhances p53- and p21-dependent downregulation of cyclin D1 hindering progression through the G1 phase of the cell cycle in hNPCs (Mishra et al.
T966 70159-70177 Sentence denotes 2010; Malik et al.
T967 70178-70184 Sentence denotes 2014).
T968 70185-70357 Sentence denotes Importantly, opioids too can affect the genesis of neurons and glia during maturation or in the adult directly via convergent pathways (Hauser and Knapp 2018; Kibaly et al.
T969 70358-70486 Sentence denotes 2018) suggesting yet another site of opioid and HIV interactions in dysregulating the creation and fate of new neurons and glia.
T970 70487-70584 Sentence denotes Few studies have examined the interplay between opioids, neural progenitors and HIV/HIV proteins.
T971 70585-70818 Sentence denotes Sustained exposure (4 d) to morphine (500 nM) and Tat1–72 (100 nM) decreased the viability of MOR-expressing striatal glial precursors, and to a lesser extent astrocytes, and this coincided with caspase-3 activation (Khurdayan et al.
T972 70819-70825 Sentence denotes 2004).
T973 70826-71040 Sentence denotes By contrast, comparably administered morphine or Tat alone was sufficient to decrease the viability of immature glia/glial progenitors in spinal cord cultures, while Tat and morphine failed to interact (Buch et al.
T974 71041-71047 Sentence denotes 2007).
T975 71048-71277 Sentence denotes Collectively, these findings were the first to indicate that opioid and/or Tat could enhance programmed cell death in subpopulations of glial precursors in a developmentally regulated and region-dependent manner (Khurdayan et al.
T976 71278-71295 Sentence denotes 2004; Buch et al.
T977 71296-71302 Sentence denotes 2007).
T978 71303-71596 Sentence denotes In human glial progenitors, co-administering morphine (500 nM) increased the antiproliferative effects of Tat (12–48 h) or conditioned medium from HIV-1SF162-infected MDMs (12 h), while paradoxically reversing the antiproliferative effects from HIV-1IIIB conditioned medium (12 h) (Hahn et al.
T979 71597-71603 Sentence denotes 2012).
T980 71604-71812 Sentence denotes In these studies, Tat or HIV exposure reduced the proliferation of Sox2+ and Olig2+ undifferentiated glial and oligodendroglial progenitors, respectively, while progenitor viability was unchanged (Hahn et al.
T981 71813-71819 Sentence denotes 2012).
T982 71820-72091 Sentence denotes In human neural progenitor cells (hNPCs), sustained infection with R5-tropic HIVBaL increased the proliferation and premature differentiation of hNPCs into both neurons and astrocytes, and both measures were significantly enhanced by morphine co-exposure (Balinang et al.
T983 72092-72098 Sentence denotes 2017).
T984 72099-72154 Sentence denotes Importantly, immunoneutralizing antibodies (Hahn et al.
T985 72155-72216 Sentence denotes 2012) or the selective antagonist, maraviroc (Balinang et al.
T986 72217-72390 Sentence denotes 2017), were able to significantly attenuate the consequences of R5-tropic HIV infection on hNPC differentiation and fate confirming a direct role of CCR5 in these processes.
T987 72391-72559 Sentence denotes Lastly, decreases in the proliferation of hNPCs seen with morphine and Tat are, in part, regulated by ERK1/2-dependent increases in p53 and p21 expression (Malik et al.
T988 72560-72652 Sentence denotes 2014) and can be modulated by PDGF BB suggesting a possible therapeutic target (Malik et al.
T989 72653-72659 Sentence denotes 2011).
T990 72660-72854 Sentence denotes Thus, morphine can exaggerate R5-tropic HIV-induced alterations in the maturation and fate of human and rodent NPCs, thereby further disrupting the balance of neural cell types and CNS function.
T991 72856-72923 Sentence denotes Matters Needing Further Consideration in Opioid and HIV Comorbidity
T992 72924-73056 Sentence denotes The interplay of complex host and viral genetic differences is likely to play a huge role in determining pathologic outcomes in PWH.
T993 73057-73117 Sentence denotes For example, differences in HIV strains/variants (Rao et al.
T994 73118-73177 Sentence denotes 2013) and human/host genetic variability (Proudnikov et al.
T995 73178-73217 Sentence denotes 2012), pharmacokinetics (Kuhlman et al.
T996 73218-73234 Sentence denotes 1996; Eap et al.
T997 73235-73296 Sentence denotes 2002; Elkader and Sproule 2005; Kharasch 2017; Kringen et al.
T998 73297-73327 Sentence denotes 2017), and sex (Zubieta et al.
T999 73328-73371 Sentence denotes 2002; Taylor and Davies 2010; Venuto et al.
T1000 73372-73392 Sentence denotes 2014; Marinho et al.
T1001 73393-73447 Sentence denotes 2019) all contribute to variability in responsiveness.
T1002 73448-73537 Sentence denotes The following subsections will focus on key factors affecting opioid and HIV comorbidity.
T1003 73539-73553 Sentence denotes HIV-1 Genetics
T1004 73554-73743 Sentence denotes Genetic differences among HIV-1 variants have a significant impact on HIV transmission, disease progression, as well as the response to ARV therapy (see reviews, Geretti 2006; Taylor et al.
T1005 73744-73761 Sentence denotes 2008; Tyor et al.
T1006 73762-73784 Sentence denotes 2013; Tables 1 and 2).
T1007 73785-73890 Sentence denotes Pre-cART studies provide substantial evidence that HIV clade differences can influence HAND (Gupta et al.
T1008 73891-73911 Sentence denotes 2007; Sacktor et al.
T1009 73912-73931 Sentence denotes 2009; Boivin et al.
T1010 73932-73953 Sentence denotes 2010; McArthur et al.
T1011 73954-73970 Sentence denotes 2010; Rao et al.
T1012 73971-74077 Sentence denotes 2013), with HAND severity being highest for clade D and B strains, followed by C and A clades (Tyor et al.
T1013 74078-74084 Sentence denotes 2013).
T1014 74085-74273 Sentence denotes These findings are supported by preclinical studies in which clade B or clade C HIV-infected macrophages were intracranially injected into severe combined immunodeficient mice (SCID) mice.
T1015 74274-74403 Sentence denotes Exposure to clade B isolates induced more severe memory deficits, as well as greater astrogliosis and neuronal damage (Rao et al.
T1016 74404-74416 Sentence denotes 2008, 2013).
T1017 74417-74573 Sentence denotes In another example, the Tat dicysteine motif (CC) at positions 30 and 31, which is commonly found in clade B isolates, appears to worsen HAND (Mishra et al.
T1018 74574-74590 Sentence denotes 2008; Rao et al.
T1019 74591-74652 Sentence denotes 2013) and has been studied extensively in vitro (Ranga et al.
T1020 74653-74669 Sentence denotes 2004; Rao et al.
T1021 74670-74686 Sentence denotes 2008; Zou et al.
T1022 74687-74723 Sentence denotes 2011; Krishnan and Chatterjee 2015).
T1023 74724-74823 Sentence denotes Clade B Tat is more intrinsically cytotoxic to primary neurons in vitro than clade C Tat (Li et al.
T1024 74824-74845 Sentence denotes 2008; Campbell et al.
T1025 74846-74862 Sentence denotes 2011; Zou et al.
T1026 74863-74966 Sentence denotes 2011), resulting in increased proinflammatory cytokine production (e.g., IL-6 and TNF-α) (Gandhi et al.
T1027 74967-75036 Sentence denotes 2009) and monocyte recruitment/migration into the brain (Ranga et al.
T1028 75037-75053 Sentence denotes 2004; Rao et al.
T1029 75054-75111 Sentence denotes 2008), and increased disruption of the BBB (Gandhi et al.
T1030 75112-75118 Sentence denotes 2010).
T1031 75119-75318 Sentence denotes Similarly, the production of the inflammatory mediators prostaglandin E2 and the thromboxane A2 receptor by astrocytes is more significantly increased by clade B than clade C gp120 (Samikkannu et al.
T1032 75319-75325 Sentence denotes 2011).
T1033 75326-75435 Sentence denotes Sequence and structural alterations in gp120 have been demonstrated between clades B and C (Gnanakaran et al.
T1034 75436-75499 Sentence denotes 2007) and potentially contribute to these observed differences.
T1035 75500-75712 Sentence denotes When considering effects of HIV clade variants in the presence of opioids, the overall toxicity in MSNs seen with clade C Tat (30% neuronal losses) was considerably less than with clade B (70% losses) (Zou et al.
T1036 75713-75719 Sentence denotes 2011).
T1037 75720-76000 Sentence denotes Although clade B HIV predominates in Western countries, future clinical longitudinal studies are necessary that employ HIV clade testing in HIV-1 infected opioid users to confirm the hypothesis that opioid interactive effects on HAND pathogenesis depend on the HIV clade assessed.
T1038 76001-76091 Sentence denotes Besides HIV genetic diversity, differences in HIV tropism add another level of complexity.
T1039 76092-76227 Sentence denotes Morphine interactions can differ significantly between X4 and R5-tropic gp120 variants depending on the outcome measure (El-Hage et al.
T1040 76228-76251 Sentence denotes 2011b; Podhaizer et al.
T1041 76252-76273 Sentence denotes 2012; Balinang et al.
T1042 76274-76290 Sentence denotes 2017; Kim et al.
T1043 76291-76297 Sentence denotes 2018).
T1044 76298-76551 Sentence denotes Increased infectivity in the presence of morphine was noted for the R5-tropic HIV-1SF162 strain in a human hepatoma Huh7.5.1 cell line model, whereas the infectivity rate with the X4-tropic HIV-1LAI/IIIB strain was unaffected by morphine (El-Hage et al.
T1045 76552-76559 Sentence denotes 2011b).
T1046 76560-76712 Sentence denotes To date, no clinical studies have assessed whether opioid interactions with R5- or R4-preferring HIV strains differentially impact the severity of HAND.
T1047 76713-76918 Sentence denotes However, the findings from preclinical studies indicate that HIV-1 strain-specific differences are critical determinants in shaping both the timing and pattern of neurotoxic interactions with opioid drugs.
T1048 76920-76933 Sentence denotes Host Genetics
T1049 76934-77110 Sentence denotes Host genetic variability can be a major determinant in individual susceptibility to HIV infectivity and may influence neuroHIV progression in the context of opiate co-exposure.
T1050 77111-77206 Sentence denotes The importance of CCR5 for HIV infectivity and polymorphisms in this gene are well established.
T1051 77207-77469 Sentence denotes Individuals who are homozygous in the CCR5 gene (CCR5Δ32) are highly resistant to infection by CCR5- (R5-) tropic HIV as demonstrated by individuals heterozygous for CCR5Δ32 who display partial resistance to infection and slower disease progression (Huang et al.
T1052 77470-77486 Sentence denotes 1996; Liu et al.
T1053 77487-77507 Sentence denotes 1996; van Rij et al.
T1054 77508-77514 Sentence denotes 1999).
T1055 77515-77673 Sentence denotes Besides CCR5, polymorphisms of other chemokine co-receptors and/or their cognate ligands have been implicated in HIV infectivity, including CCR2 (Smith et al.
T1056 77674-77696 Sentence denotes 1997; Kostrikis et al.
T1057 77697-77720 Sentence denotes 1998), CCL5 (Liu et al.
T1058 77721-77743 Sentence denotes 1999; McDermott et al.
T1059 77744-77777 Sentence denotes 2000), and CXCL12 (Winkler et al.
T1060 77778-77784 Sentence denotes 1998).
T1061 77785-77990 Sentence denotes Authoritative reviews on other gene polymorphisms that modify HIV infectivity and disease progression have been published (Lama and Planelles 2007; Singh and Spector 2009; Chatterjee 2010; Aouizerat et al.
T1062 77991-77997 Sentence denotes 2011).
T1063 77998-78215 Sentence denotes Gene polymorphisms of opioid (OPRM1 and OPRK1) and non-opioid (e.g., DRD1 and DRD2) drug/neurotransmitter receptor genes are associated with altered HIV infectivity, viral loads and CD4+ cell counts (Proudnikov et al.
T1064 78216-78234 Sentence denotes 2012; Regan et al.
T1065 78235-78254 Sentence denotes 2012; Jacobs et al.
T1066 78255-78278 Sentence denotes 2013; Proudnikov et al.
T1067 78279-78297 Sentence denotes 2013; Dever et al.
T1068 78298-78304 Sentence denotes 2014).
T1069 78305-78386 Sentence denotes Not only do MORs mediate the behavioral consequences of opiate abuse (Bond et al.
T1070 78387-78405 Sentence denotes 1998; Szeto et al.
T1071 78406-78424 Sentence denotes 2001; Ikeda et al.
T1072 78425-78443 Sentence denotes 2005; Kreek et al.
T1073 78444-78459 Sentence denotes 2005; Xu et al.
T1074 78460-78671 Sentence denotes 2014b), but the ability of MOR to modulate HIV chemokine co-receptor signaling through cross desensitization or through direct molecular interactions suggest MOR may influence HIV infectivity at multiple levels.
T1075 78672-78913 Sentence denotes The unique ability of MOR to modulate HIV co-receptor function, prompted inquiry regarding whether variants of the OPRM1 gene (polymorphisms or splicing variants) might differentially effect HIV infectivity and/or opiate addictive behaviors.
T1076 78914-79101 Sentence denotes In a sample of 1031 HIV-1-infected women, 18 OPRM1 polymorphisms were significantly associated with decreases or increases in HIV infectivity and responsiveness to cART (Proudnikov et al.
T1077 79102-79108 Sentence denotes 2012).
T1078 79109-79216 Sentence denotes Other gene polymorphisms, such as enzymes affecting drug metabolism (Meyer and Zanger 1997; Benowitz et al.
T1079 79217-79334 Sentence denotes 2006) and other neurochemical systems (Herman and Balogh 2012; Koob and Volkow 2016) can also affect drug dependence.
T1080 79335-79496 Sentence denotes The A118G variant of OPRM1 alters the regulation of proinflammatory cytokine secretion (i.e., TNF-α, IL-10, IFN-γ) from peripheral immune cells (Matsunaga et al.
T1081 79497-79503 Sentence denotes 2009).
T1082 79504-79627 Sentence denotes Overall, these findings suggest that polymorphisms in MOR ligands/genes (OPRM1) can influence the pathophysiology of HIV-1.
T1083 79628-79732 Sentence denotes Nineteen different OPRM1 spliced variants have been described in humans (Pasternak 2004, 2014; Xu et al.
T1084 79733-79749 Sentence denotes 2014a; Lu et al.
T1085 79750-79756 Sentence denotes 2015).
T1086 79757-79850 Sentence denotes OPRM1 alternative splicing may also influence susceptibility to HIV-1 infection (Dever et al.
T1087 79851-79863 Sentence denotes 2012, 2014).
T1088 79864-80140 Sentence denotes Although many variants are thought to be non-functional and fail to traffic from the endoplasmic reticulum, increasing evidence suggests they may oligomerize other G Protein-coupled receptors or bind chaperones to assist in trafficking to the plasma membrane (Samoshkin et al.
T1089 80141-80157 Sentence denotes 2015; Zhu et al.
T1090 80158-80164 Sentence denotes 2019).
T1091 80165-80339 Sentence denotes Quantitative and qualitative differences in human MOR splice variant expression levels have been noted across different CNS cell types following exposure to HIV (Dever et al.
T1092 80340-80352 Sentence denotes 2012, 2014).
T1093 80353-80439 Sentence denotes Interestingly, an excitatory, MOR-1 K splice variant, that couples to GαS (Gris et al.
T1094 80440-80506 Sentence denotes 2010) is preferentially expressed in human astroglia (Dever et al.
T1095 80507-80593 Sentence denotes 2012) and has been shown to correlate with HIVE and cognitive impairment (Dever et al.
T1096 80594-80606 Sentence denotes 2012, 2014).
T1097 80608-80661 Sentence denotes MOR and Chemokine Receptor Interactions (CCR5, CXCR4)
T1098 80662-80926 Sentence denotes The ability of opiates to modulate HIV infection and HIV neuropathogenesis/disease progression may be partly due to the interactive effects seen between the opioid and chemokine receptors, specifically MOR and CCR5 or CXCR4 (Rogers and Peterson 2003; Steele et al.
T1099 80927-80945 Sentence denotes 2003; Szabo et al.
T1100 80946-80975 Sentence denotes 2003; Festa and Meucci 2012).
T1101 80976-81108 Sentence denotes The potential mechanisms for this interaction can include heterologous cross-desensitization via downstream signaling (Rogers et al.
T1102 81109-81128 Sentence denotes 2000; Steele et al.
T1103 81129-81146 Sentence denotes 2002; Song et al.
T1104 81147-81259 Sentence denotes 2011) and/or potentially via direct opioid-chemokine receptor dimeric or heteromeric interactions (Suzuki et al.
T1105 81260-81277 Sentence denotes 2002; Chen et al.
T1106 81278-81306 Sentence denotes 2004; Nash and Meucci 2014).
T1107 81307-81431 Sentence denotes MOR and DOR activation can heterologously desensitize CCR5 responsiveness to CCL3, CCL4, and CCL5 in monocytes (Grimm et al.
T1108 81432-81450 Sentence denotes 1998; Szabo et al.
T1109 81451-81468 Sentence denotes 2003; Chen et al.
T1110 81469-81475 Sentence denotes 2004).
T1111 81476-81615 Sentence denotes The cross-desensitization appears to be regulated by MOR-dependent PKCζ activation and CCR5 phosphorylation and downregulation (Song et al.
T1112 81616-81622 Sentence denotes 2011).
T1113 81623-81795 Sentence denotes Alternatively, MOR-induced downregulation of CCL2 and CCL4 mRNA reciprocally upregulates the expression of their associated receptors, CCR2b, CCR3, and CCR5 (Mahajan et al.
T1114 81796-81802 Sentence denotes 2005).
T1115 81803-82063 Sentence denotes A previous study reported significant upregulation of CCR5 and CXCR4 expression in CD14 monocytes with [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), a MOR ligand, exposure with enhanced replication of both X4- and R5-tropic viral strains of HIV (Steele et al.
T1116 82064-82070 Sentence denotes 2003).
T1117 82071-82350 Sentence denotes For CXCR4, bidirectional heterologous desensitization is less evident with MOR but has been reported for KOR, with Ca2+ signaling experiments suggesting that cross-desensitization occurs within seconds of KOR or CXCR4 activation in a concentration-dependent manner (Finley et al.
T1118 82351-82357 Sentence denotes 2008).
T1119 82358-82590 Sentence denotes Thus, opiates acting at different opioid receptors in the presence of HIV appear to activate chemokine receptor signaling and can contribute to the synergistic effects of HIV and opioid drug co-exposure seen in neuroHIV progression.
T1120 82591-82742 Sentence denotes The ability of opiates to modulate CCR5 expression in the CNS has been demonstrated to occur in various cell types, including microglia (Bokhari et al.
T1121 82743-82780 Sentence denotes 2009), and astrocytes (Mahajan et al.
T1122 82781-82787 Sentence denotes 2002).
T1123 82788-83011 Sentence denotes Specifically, in astrocytes MOR activation enhanced CCR5 and additional HIV-1 entry co-receptor (CCR3 and CXCR2) expression, whereas local production of HIV-1 protective chemokines (IL-8, CCL4) was inhibited (Mahajan et al.
T1124 83012-83018 Sentence denotes 2002).
T1125 83019-83161 Sentence denotes Deletion of CCR5 significantly attenuates morphine-induced increases in astrocyte CCL2 immunoreactivity in Tat transgenic mice (El-Hage et al.
T1126 83162-83178 Sentence denotes 2008a) (Fig. 1).
T1127 83179-83474 Sentence denotes Interestingly, the proportion of CCL2 immunoreactive macrophages/microglia in CCL5(−/−) mice after Tat and morphine co-administration still showed a significant upregulation, suggesting CCL5 regulates Tat and morphine-induced increases in CCL2 in astrocytes, but not in microglia (El-Hage et al.
T1128 83475-83491 Sentence denotes 2008a) (Fig. 1).
T1129 83492-83749 Sentence denotes The cell type specific interactions between CCR5 and MOR were noted when using a bivalent ligand derivative of maraviroc linked to an opioid antagonist, naltrexone, with HIV-1 entry being significantly blocked in astrocytes but not microglia (El-Hage et al.
T1130 83750-83765 Sentence denotes 2013) (Fig. 5).
T1131 83766-83971 Sentence denotes Interestingly, maraviroc’s antiviral effects are completely negated in both astrocytes and microglia when morphine is present suggesting that maraviroc therapy may not be effective with opiate co-exposure.
T1132 83972-84265 Sentence denotes Importantly, unlike maraviroc, the bivalent compound blocked HIV entry in astrocytes irrespective of morphine treatment, while exacerbating HIV infectivity in morphine co-exposed microglia and revealing fundamental differences in the regulation of MOR and CCR5 expression in these glial types.
T1133 84266-84531 Sentence denotes Whereas, MOR and CCR5 expression appear to be similarly regulated in astrocytes, their expression patterns in microglia appear to be inversely correlated upon HIV and/or morphine exposure, with CCR5 being expressed at much higher levels than MOR (see El-Hage et al.
T1134 84532-84538 Sentence denotes 2013).
T1135 84539-84768 Sentence denotes The differential effects of the bivalent ligand in astrocytes compared to microglia might be due to the fact that the expression levels of MOR and CCR5 are differentially regulated by HIV in each of the cell types (El-Hage et al.
T1136 84769-84786 Sentence denotes 2013; Yuan et al.
T1137 84787-84806 Sentence denotes 2013; Arnatt et al.
T1138 84807-84813 Sentence denotes 2016).
T1139 84814-85098 Sentence denotes Fig. 5 Differential inhibition of HIV-1 entry into human glia by maraviroc and a bivalent CCR5-MOR antagonist (BVL) with cell-specific interactions in combination with morphine. (a) Construction of a MOR-CCR5 heterodimer model in a membrane (gray), and aqueous surrounds (red) system.
T1140 85099-85434 Sentence denotes The green protein represents MOR and the blue protein represents CCR5, while the bivalent ligand is colored in yellow. (b) Different binding pocket (green) for the triazole moiety of the bivalent ligand yellow) at 0 ns and 6.0 ns. (c) Construction of a chemical probe that interacts with both the MOR and CCR5 receptors simultaneously.
T1141 85435-85608 Sentence denotes To monitor HIV-1 infection (d) astrocytes and (e) microglia were transfected with a pBlue3′LTR-luc reporter sensitive to Tat expression and luciferase activity was measured.
T1142 85609-85750 Sentence denotes Data indicate that maraviroc’s antiviral effects are completely negated in both astrocytes and microglia when morphine is present (red bars).
T1143 85751-85873 Sentence denotes Interestingly, unlike maraviroc, the bivalent compound blocked HIV entry in astrocytes irrespective of morphine treatment.
T1144 85874-85991 Sentence denotes By contrast, the bivalent antagonist exacerbated HIV infectivity in microglia in the presence of morphine (red bars).
T1145 85992-86160 Sentence denotes The findings reveal fundamental differences in co-regulation of MOR and CCR5 expression in astroglia and microglia upon HIV and/or morphine exposure (see El-Hage et al.
T1146 86161-86167 Sentence denotes 2013).
T1147 86168-86608 Sentence denotes Values are luminescence intensity ± SEM from 3 to 5 independent experiments at 18 h post-infection (*p < 0.005 vs. un-infected cells; $p < 0.05 vs. R5 HIV-1; #p < 0.05 vs. R5 + morphine (M); ¶p < 0.05 vs. R5 + maraviroc (MVC); §p < 0.05 vs. R5 + M + MVC; ¥p < 0.05 vs. R5 + M + MVC + naltrexone). (a–b) Modified and reprinted with permission from Arnatt et al. (2016). (c–e) Modified and reprinted with permission from El-Hage et al. (2013)
T1148 86609-86918 Sentence denotes The importance of CCR5 activation in glia, but not neurons, in mediating the neurotoxic effects of morphine-dependent MOR activation is further supported in a recent study demonstrating that the loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions (Kim et al.
T1149 86919-86925 Sentence denotes 2018).
T1150 86926-87093 Sentence denotes Similarly, short-duration (5 d) maraviroc pre-treatment also eliminated neurotoxicity and attenuated neuronal increases in [Ca2+]i caused by Tat ± morphine (Kim et al.
T1151 87094-87100 Sentence denotes 2018).
T1152 87101-87145 Sentence denotes Selectively deleting either CCR5 (Kim et al.
T1153 87146-87170 Sentence denotes 2018) or MOR (Zou et al.
T1154 87171-87268 Sentence denotes 2011) from glia completely protects MSNs from morphine’s ability to exacerbate Tat neurotoxicity.
T1155 87269-87497 Sentence denotes However, deleting CCR5 from glia only revealed a paradoxical neuroprotective effect of morphine on Tat toxicity that is mediated by opioid receptors and appears to involve alterations in BDNF processing and signaling (Kim et al.
T1156 87498-87504 Sentence denotes 2018).
T1157 87506-87585 Sentence denotes Enhanced Mature BDNF (mBDNF) Produced by CCR5 Deficient Glia is Neuroprotective
T1158 87586-87763 Sentence denotes Mature BDNF (mBDNF) activates tyrosine receptor kinase B (TrkB) and is neuroprotective, while the precursor to BDNF, pro-BDNF, binds p75NTR and can activate cell death pathways.
T1159 87764-87920 Sentence denotes Based on findings of significant, reversible reductions in glially produced BDNF after exposure to HIV-infected cell supernatant ± morphine (Masvekar et al.
T1160 87921-87993 Sentence denotes 2014), altered BDNF processing in lymphocytes from PWH (Avdoshina et al.
T1161 87994-88053 Sentence denotes 2011), and following exposure to HIV-1 gp120 (Bachis et al.
T1162 88054-88219 Sentence denotes 2012), the pro-BDNF:mBDNF ratio was analyzed in supernatants from wild-type vs. CCR5-null striatal glial cultures exposed to Tat ± morphine for 6 or 24 h (Kim et al.
T1163 88220-88235 Sentence denotes 2018) (Fig. 6).
T1164 88236-88460 Sentence denotes CCR5-deficiency reduced this ratio by over 2-fold in cells treated with Tat and morphine after 6 h (Fig. 6), indicating a relative increase in mBDNF that may partially protect neurons in the CCR5-deficient glial environment.
T1165 88461-88599 Sentence denotes Fig. 6 Role of CCR5 and BDNF in mediating HIV-1 Tat and morphine-induced interactive cytotoxicity in striatal medium spiny neurons (MSNs).
T1166 88600-88885 Sentence denotes A proportion of glial fibrillary acidic protein (GFAP)-immunolabeled striatal astrocytes display punctate patterns of μ-opioid receptor (MOR) (a) and CCR5 (b) (43.8 ± 2.4%) immunofluorescence—with some faint immunoreactivity extending into the cell processes; scale bars = 10 μm (a-b).
T1167 88886-88974 Sentence denotes HIV-1 Tat and morphine are no longer toxic to MSNs when CCR5 is deleted from glia (c-f).
T1168 88975-89223 Sentence denotes In C57BL/J wild-type mixed glia-MSN co-cultures, Tat is neurotoxic (*p = 0.001 vs. controls), and co-exposure to morphine enhanced Tat-induced toxicity over a 72-h period (**p < 0.001 vs. controls, p < 0.05 vs. Tat) and antagonized by naloxone (c).
T1169 89224-89298 Sentence denotes Naloxone or morphine by themselves had no effect on neuronal survival (c).
T1170 89299-89523 Sentence denotes In co-cultures with CCR5-deficit glia and wild-type neurons, exposure to Tat by itself is significantly toxic (*p < 0.001 vs. controls); however, the enhanced toxicity seen with combined morphine exposure was eliminated (d).
T1171 89524-89646 Sentence denotes Unexpectedly, morphine co-treatment entirely abolished the toxic effects of Tat, restoring MSN survival to control levels.
T1172 89647-89848 Sentence denotes Pre-treatment with naloxone re-established Tat toxicity, suggesting that the paradoxical protective effects of morphine are mediated by MOR (or perhaps another opioid receptor type) (d) (see Kim et al.
T1173 89849-89855 Sentence denotes 2018).
T1174 89856-89981 Sentence denotes The neurotoxic patterns seen in CCR5-deficient MSNs and wild-type glial co-cultures are similar to wild-type co-cultures (e).
T1175 89982-90109 Sentence denotes Co-cultures in which MSNs and glia are both deficient in CCR5 are similar to those in which CCR5 is only deficient in glia (f).
T1176 90110-90236 Sentence denotes CCR5 deletion alters the expression and processing of BDNF precursor (pro-BDNF) to mature (mBDNF) by mixed-glial cultures (g).
T1177 90237-90551 Sentence denotes BDNF is expressed by both astroglia and microglia; mBDNF is neuroprotective, while pro-BDNF can promote programmed cell death. mBDNF and pro-BDNF levels were analyzed in conditioned media from wild-type or CCR5-deficient mixed glia treated with Tat ± morphine after 6 h or 24 h to assess pro-BDNF and mBDNF levels.
T1178 90552-90717 Sentence denotes The proportion of pro-BDNF/mBDNF levels was significantly higher in wild-type compared to CCR5-null glia at 24 h (lower row; g), suggesting reduced neuronal support.
T1179 90718-90920 Sentence denotes Although morphine significantly decreased pro-BDNF in CCR5-deficient glia at both 6 h and 24 h compared to control levels (not shown), the pro-BDNF/mBDNF ratios were unaltered (upper and lower rows; g).
T1180 90921-91159 Sentence denotes By contrast, combined Tat and morphine significantly decreased the pro-BDNF/mBDNF ratio at 6 h, suggesting transient protection with CCR5 deficiency that was not fully sustained at 24 h (p = 0.17) (*p < 0.05, wild-type vs. CCR5-null) (g).
T1181 91160-91243 Sentence denotes Exogenous mBDNF is neuroprotective against combined Tat and morphine treatment (h).
T1182 91244-91385 Sentence denotes Wild-type, mixed glial-MSN co-cultures were treated with mBDNF and Tat, or combined Tat and morphine (represented by dotted survival curves).
T1183 91386-91506 Sentence denotes Tat alone was neurotoxic (*p < 0.05), and Tat was significantly worsened by co-exposing MSNs to morphine (**p < 0.0001).
T1184 91507-91700 Sentence denotes The addition of mBDNF (50 ng/ml; 72 h) fully protected MSNs against combined Tat and morphine toxicity, but only tended to protect (albeit not significantly) MSNs treated with Tat alone (#)(h).
T1185 91701-92004 Sentence denotes Overall, the results in c-h suggest (1) an important role for glial CCR5 in mediating HIV-1 and opiate neurotoxic interactions, (2) that CCR5 deficiency influences signaling through MOR, and (3) that CCR5 (and perhaps MOR) act via a BDNF intermediary to promote or obstruct neuronal survival (Kim et al.
T1186 92005-92237 Sentence denotes 2018). (a-b) Modified and reprinted with permission from Podhaizer et al. (2012). (c-h) Modified and reprinted from Kim et al. (2018), which is an open access article distributed under the terms of the Creative Commons CC BY license
T1187 92238-92466 Sentence denotes Exogenous mBDNF treatment has been found to mimic the pro-survival effect of glial CCR5 deficiency against Tat ± morphine, and its neuroprotective effects have been supported in other neurodegenerative disease models (Cai et al.
T1188 92467-92482 Sentence denotes 2014; Xu et al.
T1189 92483-92489 Sentence denotes 2018).
T1190 92490-92633 Sentence denotes Collectively, the findings suggest that the loss of CCR5 may fundamentally change MOR signaling in HIV-exposed glia in a BDNF-dependent manner.
T1191 92634-92834 Sentence denotes Thus, overall the interaction of opioid and chemokine receptors, specifically MOR and CCR5, may alter the neuropathogenesis of HIV in a qualitatively unique manner not seen with either disorder alone.
T1192 92836-92880 Sentence denotes Does HIV Alter the Endogenous Opioid System?
T1193 92881-93073 Sentence denotes Little is known about the effects of HIV on the endogenous opioid system and the extent to which HIV might disrupt the expression and function of opioid peptides and receptors, and vice versa.
T1194 93074-93289 Sentence denotes Because opiate drugs act exclusively by mimicking endogenous peptides and engaging opioid receptors, it is likely that endogenous opioids also interact with HIV to some extent to affect the pathogenesis of neuroHIV.
T1195 93290-93545 Sentence denotes The endogenous opioid system comprises three originally described opioid receptors, MOR, KOR, and DOR and endogenous opioid peptide-expressing genes proopiomelanocortin (POMC), prodynorphin (PDYN), and proenkephalin (PENK) (Brownstein 1993; Trescot et al.
T1196 93546-93678 Sentence denotes 2008; Bodnar 2010; Pasternak and Pan 2013), as well as a fourth receptor (OPRN1) and peptide (nociceptin/orphanin FQ) family member.
T1197 93679-93842 Sentence denotes The endogenous opioid system has a fundamental role in pain regulation and has been implicated in the pathophysiology of various neurologic diseases (Nandhu et al.
T1198 93843-93864 Sentence denotes 2010; Sauriyal et al.
T1199 93865-93924 Sentence denotes 2011; Benarroch 2012) and in pain management (Bruehl et al.
T1200 93925-93931 Sentence denotes 2013).
T1201 93932-94037 Sentence denotes Postmortem clinical studies indicate the endogenous opioid system is disrupted in neuroHIV (Gelman et al.
T1202 94038-94058 Sentence denotes 2012; Yuferov et al.
T1203 94059-94065 Sentence denotes 2014).
T1204 94066-94142 Sentence denotes Specifically, OPRK1 mRNA is significantly upregulated in PWH (Yuferov et al.
T1205 94143-94203 Sentence denotes 2014) and in transgenic neuroHIV rodent models (Chang et al.
T1206 94204-94224 Sentence denotes 2007; Fitting et al.
T1207 94225-94373 Sentence denotes 2010b) potentially as a compensatory neuroprotective function in response to inflammatory processes in the presence of HIV infection (Yuferov et al.
T1208 94374-94380 Sentence denotes 2014).
T1209 94381-94564 Sentence denotes The upregulation of mRNA coding OPRK1 is triggered by factors released by activated macrophages and glia and is supported by mechanistic studies in dorsal root ganglia (Puehler et al.
T1210 94565-94588 Sentence denotes 2006; Gabrilovac et al.
T1211 94589-94595 Sentence denotes 2012).
T1212 94596-94814 Sentence denotes Since leukocytes, including macrophages, can express β-endorphin and enkephalins, it is important to consider the potential influence of leukocyte-derived endogenous opioid peptides in neuroinflammation (Rittner et al.
T1213 94815-94821 Sentence denotes 2001).
T1214 94822-94992 Sentence denotes Granulocytes express about 10-fold higher levels of β-endorphin, a preferential MOR and lower affinity KOR endogenous ligand, than lymphocytes (Pallinger and Csaba 2008).
T1215 94993-95089 Sentence denotes Increases in β-endorphin expression by peripheral blood mononuclear cells (PBMCs) (Gironi et al.
T1216 95090-95109 Sentence denotes 2000; Gironi et al.
T1217 95110-95178 Sentence denotes 2003), coincide with inflammation and relapse in multiple sclerosis.
T1218 95179-95529 Sentence denotes Moreover, increases in inflammatory cytokines, such as interleukin-1β (IL-1β), have been demonstrated to differentially increase the expression of proenkephalin transcripts in primary astrocytes cultured from different brain regions (Ruzicka and Akil 1997) and increase IL-10-stimulated β-endorphin expression in cultured primary microglia (Wu et al.
T1219 95530-95536 Sentence denotes 2017).
T1220 95537-95630 Sentence denotes Interestingly, OPRM1 mRNA levels do not differ between HIV+ and HIV− subjects (Yuferov et al.
T1221 95631-95637 Sentence denotes 2014).
T1222 95638-95742 Sentence denotes PENK was downregulated in brain samples from 446 PWH compared to 67 HIV negative patients (Gelman et al.
T1223 95743-95749 Sentence denotes 2012).
T1224 95750-95854 Sentence denotes The subjects with HIV also expressed higher levels of interferon regulatory factor 1 (IRF1) transcripts.
T1225 95855-96036 Sentence denotes The idea that higher opioid peptide expression levels are neuroprotective has been supported in human studies and experimental animal models (Solbrig and Koob 2004; Sarkisyan et al.
T1226 96037-96053 Sentence denotes 2015; Nam et al.
T1227 96054-96121 Sentence denotes 2019) suggesting the reductions in PENK expression are deleterious.
T1228 96122-96310 Sentence denotes The effects of HIV Tat on expression levels of opioid peptide and receptor levels depend on the individual CNS region involved as well as levels of tat transgene expression (Fitting et al.
T1229 96311-96318 Sentence denotes 2010b).
T1230 96319-96616 Sentence denotes For example, while PDYN mRNA levels were significantly reduced in the hippocampus and striatum of Tat-expressing mice, POMC was only significantly reduced by Tat induction in the striatum and PENK mRNA levels in the hippocampus were affected by chronic (but not acute) Tat exposure (Fitting et al.
T1231 96617-96624 Sentence denotes 2010b).
T1232 96625-96783 Sentence denotes Thus, HIV may alter the endogenous opioid system by modifying the expression of opioid peptides and their receptors in a brain- and cell-type specific manner.
T1233 96784-96886 Sentence denotes The consequences of HIV-1-dependent alterations in the endogenous opioid system to HAND are uncertain.
T1234 96888-96927 Sentence denotes Questions Remaining – Future Directions
T1235 96929-96984 Sentence denotes Modeling the Pharmacology of Opioid Self-Administration
T1236 96985-97207 Sentence denotes Opiate self-administration as seen with addiction can have different CNS consequences than “steady-state” (e.g., continuous via a pump or time-release drug implant) exposure to the same drug (Kreek 1987, 2001; Kreek et al.
T1237 97208-97323 Sentence denotes 2002), and we predict the pharmacokinetic differences in opiate exposure will markedly impact neuroHIV progression.
T1238 97324-97579 Sentence denotes Differential effects based on “on-off” and “steady-state” drug administration schedules have been reported for the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, the endogenous opioid system, and the dopamine system (Kreek 1973; Kreek et al.
T1239 97580-97599 Sentence denotes 2002; George et al.
T1240 97600-97606 Sentence denotes 2012).
T1241 97607-97801 Sentence denotes Acute opiate exposure typically activates the HPA axis, corticotropin releasing factor, and peripheral steroidogenesis in a species-dependent manner (Koob and Kreek 2007; Cleck and Blendy 2008).
T1242 97802-97928 Sentence denotes Alternatively, chronic self-administration of short-acting opiates suppresses diurnal cortisol rhythmicity (Facchinetti et al.
T1243 97929-97947 Sentence denotes 1984; Vuong et al.
T1244 97948-98069 Sentence denotes 2010), while opiate withdrawal typically evokes HPA activation (Culpepper-Morgan and Kreek 1997; Kreek 2007; Paris et al.
T1245 98070-98076 Sentence denotes 2020).
T1246 98077-98267 Sentence denotes The daily, repeated bouts of relative withdrawal seen with opiate addiction cause sustained HPA activation, stress (Koob and Kreek 2007; Koob 2020), and immune suppression (Eisenstein 2019).
T1247 98268-98419 Sentence denotes Importantly, maintenance therapy with the long-acting drug methadone achieves steady-dose opiate levels and normalization of the HPA axis (Kreek 1973).
T1248 98420-98552 Sentence denotes Further, it is known that HIV infection significantly alters the HPA axis, due to CNS toxicity and cytokine production (Costa et al.
T1249 98553-98611 Sentence denotes 2000; George and Bhangoo 2013; Chrousos and Zapanti 2014).
T1250 98612-98793 Sentence denotes Additionally, the nature of opiate exposure in the context of neuroHIV needs to be considered as it may induce different outcomes on neurotransmitter metabolism and gene expression.
T1251 98794-98937 Sentence denotes Specifically, the NAc shell demonstrates molecular and structural changes associated with intravenous heroin self-administration (Jacobs et al.
T1252 98938-98944 Sentence denotes 2005).
T1253 98945-99252 Sentence denotes Moreover, earlier studies have reported differential alterations in the turnover rates of various neurotransmitters for active versus passive morphine administration, including dopamine, serotonin, γ-aminobutyric acid (GABA), acetylcholine, aspartate, and glutamate during exposure to morphine (Smith et al.
T1254 99253-99265 Sentence denotes 1982, 1984).
T1255 99266-99544 Sentence denotes The disruptions were noticed specifically in brain regions involved in reinforcement processes, including the NAc, frontal cortex, and striatum, and encompassed increased dopamine and norepinephrine levels and turnover, which are central in opiate reward processes (Smith et al.
T1256 99545-99551 Sentence denotes 1982).
T1257 99552-99793 Sentence denotes Heroin abuse is known to downregulate dopaminergic activity in the NAc and may reflect a compensatory reduction in of dopamine biosynthesis in response to excessive dopaminergic stimulation resulting from chronic opiate exposure (Kish et al.
T1258 99794-99800 Sentence denotes 2001).
T1259 99801-99885 Sentence denotes Additionally, HIV is known to interfere with dopamine neurotransmission (Nath et al.
T1260 99886-99907 Sentence denotes 2000b; Gaskill et al.
T1261 99908-100018 Sentence denotes 2017) causing reductions in presynaptic dopamine terminals and dopamine transport in the striatum (Wang et al.
T1262 100019-100037 Sentence denotes 2004; Chang et al.
T1263 100038-100056 Sentence denotes 2008; Midde et al.
T1264 100057-100069 Sentence denotes 2012, 2015).
T1265 100070-100232 Sentence denotes The decline in dopamine function may exacerbate opioid abuse tendencies and drug-seeking behaviors as the rewarding effects of opioids are discounted by neuroHIV.
T1266 100234-100329 Sentence denotes Opioid Substitution Therapies and the Role of Selective/Biased Agonism in neuroHIV Pathogenesis
T1267 100330-100631 Sentence denotes Although morphine, methadone, and buprenorphine all activate MOR, each can impart different signals through MOR, related to the nature and timing of their coupling to Gα, Gβγ, β-arrestin and/or regulators of G protein signaling (RGS), since each downstream effector couples into unique cell functions.
T1268 100632-100773 Sentence denotes Functional selectivity occurs at each opioid receptor type, and for most endogenous opioid peptides at all three receptor types (Gomes et al.
T1269 100774-100780 Sentence denotes 2020).
T1270 100781-101005 Sentence denotes Moreover, opioid receptors can be expressed on a subset of virtually every cell type in the CNS—with second messenger coupling to each opioid receptor type potentially being unique, cell-type specific, and context dependent.
T1271 101006-101095 Sentence denotes Thus, the “pluridimensional” (Galandrin and Bouvier 2006; Kenakin 2011; Costa-Neto et al.
T1272 101096-101330 Sentence denotes 2016) actions of any opiate at MOR are sufficiently complicated that it is not possible to predict whether, e.g., morphine, methadone or buprenorphine, would similarly effect any aspect of neuroHIV pathology without empirical testing.
T1273 101331-101572 Sentence denotes Despite their significant use as medication-assisted therapies for treating opioid addiction, few studies have directly compared commonly used opiate substitution therapies (Bell and Strang 2020), especially in relation to HIV (Khalsa et al.
T1274 101573-101590 Sentence denotes 2006; Choi et al.
T1275 101591-101597 Sentence denotes 2020).
T1276 101598-101727 Sentence denotes Opioid substitution therapies significantly reduce the frequency of injection drug use (Kwiatkowski and Booth 2001; Pettes et al.
T1277 101728-101783 Sentence denotes 2010), decrease HIV transmission risk (MacArthur et al.
T1278 101784-101802 Sentence denotes 2012; Platt et al.
T1279 101803-101859 Sentence denotes 2016), and reduce drug-related mortality (Mathers et al.
T1280 101860-101912 Sentence denotes 2013) and the risk of opioid overdose (Volkow et al.
T1281 101913-101919 Sentence denotes 2014).
T1282 101920-102120 Sentence denotes Further, improved ARV outcomes among PWH have been reported with opioid substitution therapies, including the uptake and retention on ARV, medication adherence rates, and viral suppression (Low et al.
T1283 102121-102145 Sentence denotes 2016; Mukandavire et al.
T1284 102146-102152 Sentence denotes 2017).
T1285 102153-102348 Sentence denotes The two main medications used for opioid substitution therapy include methadone, a MOR full agonist, and buprenorphine, a MOR partial agonist and partial antagonist of KOR (Noble and Marie 2018).
T1286 102349-102629 Sentence denotes In comparison to methadone, buprenorphine has been shown to have fewer pharmacodynamic interactions with ARVs and causes less opioid withdrawal symptoms potentially due to its partial agonism on MOR, but also due to its high affinity and long duration of MOR binding (Walsh et al.
T1287 102630-102679 Sentence denotes 1994; McCance-Katz 2005; Whelan and Remski 2012).
T1288 102680-102801 Sentence denotes Further, differential proinflammatory and neurotoxic effects have been noted for various opioid treatments (Boland et al.
T1289 102802-102822 Sentence denotes 2014; Fitting et al.
T1290 102823-102845 Sentence denotes 2014b; Carvallo et al.
T1291 102846-102872 Sentence denotes 2015; Dutta and Roy 2015).
T1292 102873-102977 Sentence denotes In primary astrocytes, agonist-selective actions at MOR and KOR can be clearly demonstrated (Bohn et al.
T1293 102978-102999 Sentence denotes 2000; Belcheva et al.
T1294 103000-103021 Sentence denotes 2003; McLennan et al.
T1295 103022-103039 Sentence denotes 2008; Hahn et al.
T1296 103040-103194 Sentence denotes 2010), and we found that morphine, methadone, and buprenorphine differentially increase ROS and [Ca2+]i alone or following Tat co-exposure (Fitting et al.
T1297 103195-103202 Sentence denotes 2014b).
T1298 103203-103305 Sentence denotes Morphine can enhance HIV-1-induced production of cytokines and specifically chemokines (El-Hage et al.
T1299 103306-103338 Sentence denotes 2008a; Dave 2012; El-Hage et al.
T1300 103339-103504 Sentence denotes 2014), while other opioids including methadone, oxycodone, buprenorphine, and DAMGO can decrease inflammatory function and decrease monocyte migration (Boland et al.
T1301 103505-103526 Sentence denotes 2014; Carvallo et al.
T1302 103527-103559 Sentence denotes 2015; Jaureguiberry-Bravo et al.
T1303 103560-103581 Sentence denotes 2016; Chilunda et al.
T1304 103582-103588 Sentence denotes 2019).
T1305 103589-103891 Sentence denotes As most opiate drugs preferentially act via MOR, a potential explanation for differential interactive effects of opioids in the context of neuroHIV is the phenomenon of selective or “biased agonism”, such that different agonists can trigger distinct signaling events at the same receptor (Hauser et al.
T1306 103892-103898 Sentence denotes 2012).
T1307 103899-104040 Sentence denotes For example, coupling of MOR to Gα, Gβγ, and/or β-arrestin have been noted to differ depending on the MOR agonists involved (McPherson et al.
T1308 104041-104062 Sentence denotes 2010; Thompson et al.
T1309 104063-104084 Sentence denotes 2015; Burgueno et al.
T1310 104085-104091 Sentence denotes 2017).
T1311 104092-104294 Sentence denotes Physiologic outcomes of MOR activation in any cell type are determined by a bias for specific signaling pathways, the initial step of which is activation of G proteins and/or β-arrestin (Williams et al.
T1312 104295-104315 Sentence denotes 2013b; Violin et al.
T1313 104316-104339 Sentence denotes 2014; Suomivuori et al.
T1314 104340-104346 Sentence denotes 2020).
T1315 104347-104516 Sentence denotes The subcellular organization of GPCR signaling transduced by heterotrimeric G proteins and β-arrestin has been recently reviewed in detail (Eichel and von Zastrow 2018).
T1316 104517-104715 Sentence denotes In the context of HIV, it has been shown that selective MOR agonists such as endomorphin-1, but not DAMGO or morphine, significantly increase HIV-1 replication in infected microglia (Peterson et al.
T1317 104716-104722 Sentence denotes 1999).
T1318 104723-104940 Sentence denotes This effect might be due to an apparent bias of endomorphin-1 towards arrestin recruitment and receptor phosphorylation, which was significantly correlated with agonist-induced internalization of MOR (McPherson et al.
T1319 104941-104947 Sentence denotes 2010).
T1320 104948-105188 Sentence denotes It is suggested that ligands that display bias towards G protein-mediated pathways and away from β-arrestin 2 recruitment may have improved therapeutic profiles against the development of tolerance and dependence/addiction (McPherson et al.
T1321 105189-105195 Sentence denotes 2010).
T1322 105197-105268 Sentence denotes Opioid Effects on Antiretroviral Efficacy within the CNS and Vice Versa
T1323 105269-105342 Sentence denotes Opioid misuse has been linked to poor adherence to cART (Jeevanjee et al.
T1324 105343-105349 Sentence denotes 2014).
T1325 105350-105454 Sentence denotes However, adherence to ARV therapy improves after initiation of opioid substitution therapy (Nosyk et al.
T1326 105455-105471 Sentence denotes 2015; Low et al.
T1327 105472-105490 Sentence denotes 2016; Adams et al.
T1328 105491-105497 Sentence denotes 2020).
T1329 105498-105712 Sentence denotes Although better adherence can improve therapeutic outcomes in PWH, little information is currently available on the interaction between opioids or opioid substitution therapies and cART specifically within the CNS.
T1330 105713-105821 Sentence denotes There are several known drug-drug interactions between opioids and ARVs that affect systemic concentrations.
T1331 105822-105927 Sentence denotes The partial opioid agonist, buprenorphine, is metabolized primarily by cytochrome P450 (CYP) 3A4 and 2C8.
T1332 105928-106078 Sentence denotes Both buprenorphine and its active metabolite, norbuprenorphine, are glucuronidated by UDP-glucuronosyltransferase (UGT) 1A1 and then excreted in bile.
T1333 106079-106135 Sentence denotes Several ARVs inhibit or induce these metabolic pathways.
T1334 106136-106190 Sentence denotes However, not all interactions are clinically relevant.
T1335 106191-106492 Sentence denotes The boosted protease inhibitor combination, atazanavir/ritonavir, inhibits CYP 3A4 and UGT 1A1, leading to increases in overall systemic exposure of buprenorphine and norbuprenorphine and also results in symptoms of opioid excess, such as increased sedation and impaired cognition (McCance-Katz et al.
T1336 106493-106499 Sentence denotes 2007).
T1337 106500-106625 Sentence denotes Dose adjustments of buprenorphine are recommended when initiating therapy with atazanavir to avoid symptoms of opioid excess.
T1338 106626-106740 Sentence denotes Methadone is a full opioid substrate with multiple metabolic pathways, including CYP 3A4, 2B6, 2C19, 2C9, and 2D6.
T1339 106741-106833 Sentence denotes Several pharmacokinetic interactions are reported between methadone and protease inhibitors.
T1340 106834-106938 Sentence denotes However, withdrawal symptoms are rare, and therefore, dose adjustments are not recommended (Bruce et al.
T1341 106939-106959 Sentence denotes 2006; Meemken et al.
T1342 106960-106966 Sentence denotes 2015).
T1343 106967-107131 Sentence denotes In contrast, efavirenz and nevirapine induce CYP 3A4, resulting in decreased systemic concentrations of methadone and the development of opioid withdrawal symptoms.
T1344 107132-107276 Sentence denotes To avoid opioid withdrawal, increased methadone dosing is recommended when either efavirenz or nevirapine therapy is initiated (Marzolini et al.
T1345 107277-107296 Sentence denotes 2000; Clarke et al.
T1346 107297-107317 Sentence denotes 2001; Meemken et al.
T1347 107318-107324 Sentence denotes 2015).
T1348 107325-107477 Sentence denotes Oxycodone metabolism is inhibited by lopinavir/ritonavir, increasing oxycodone concentrations as well as the self-reported drug effects (Nieminen et al.
T1349 107478-107495 Sentence denotes 2010; Feng et al.
T1350 107496-107502 Sentence denotes 2017).
T1351 107503-107583 Sentence denotes The pharmacokinetic studies above focused on overall systemic exposure of drugs.
T1352 107584-107670 Sentence denotes Plasma concentrations, however, are not always accurate indicators of tissue exposure.
T1353 107671-107763 Sentence denotes Similarly, CNS drug exposure is often estimated based on drug concentrations within the CSF.
T1354 107764-107837 Sentence denotes However, CSF drug levels may not accurately predict brain concentrations.
T1355 107838-107974 Sentence denotes For many drugs with high efflux activities (e.g., substrates of P-gp), CSF tends to over-predict brain tissue concentrations (Liu et al.
T1356 107975-107994 Sentence denotes 2006; Friden et al.
T1357 107995-108015 Sentence denotes 2009; Kodaira et al.
T1358 108016-108028 Sentence denotes 2011, 2014).
T1359 108029-108133 Sentence denotes This could be due, in part, to differential expression of transporters at the blood-CSF barrier vs. BBB.
T1360 108134-108354 Sentence denotes In a study of the ARV drug amprenavir, concentrations of [14C]-amprenavir in CSF versus brain were 23.3 ± 11.2 and 3.33 ± 0.6 nCi/g, respectively, demonstrating overprediction of brain concentrations by CSF (Polli et al.
T1361 108355-108361 Sentence denotes 1999).
T1362 108362-108488 Sentence denotes These studies illustrate the high likelihood of misinterpreting drug brain penetration when using CSF as the surrogate marker.
T1363 108489-108683 Sentence denotes Therefore, direct measurement of brain tissue concentrations in animal models are likely to be more predictive of the interactive effects of ARVs and opioids on ARV and/or opioid brain exposure.
T1364 108684-108801 Sentence denotes A few studies have investigated the impact of opioids and ARV administration on drug concentrations within the brain.
T1365 108802-109083 Sentence denotes One study investigated the impact of 5 d continuous exposure to morphine on ARV brain concentrations (dolutegravir, lamivudine and abacavir) and demonstrated that morphine exposure resulted in regionally specific decreases in the concentrations of select ARV drugs (Leibrand et al.
T1366 109084-109272 Sentence denotes 2019) and, furthermore, that the decreases in ARV concentrations (dolutegravir and abacavir) were likely due to increased efflux by the drug efflux transport protein, P-gp (Leibrand et al.
T1367 109273-109279 Sentence denotes 2019).
T1368 109280-109384 Sentence denotes Morphine alterations in P-gp within the brain could have wide reaching impact on other CNS active drugs.
T1369 109385-109555 Sentence denotes HIV preferentially infects microglia and perivascular macrophages within the brain, although BMECs, astrocytes, and pericytes can also be infected (Kramer-Hammerle et al.
T1370 109556-109562 Sentence denotes 2005).
T1371 109563-109654 Sentence denotes Achieving optimal intracellular ARV concentrations are essential to suppress the infection.
T1372 109655-109814 Sentence denotes Few studies have examined whether ARV drugs differentially accumulate within different neural cell types and especially within cells of the neurovascular unit.
T1373 109815-110133 Sentence denotes Although nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are efficacious in inhibiting viral replication within monocyte-derived macrophages, only a few drugs within each ARV class can effectively inhibit viral replication within astrocytes (Gray et al.
T1374 110134-110218 Sentence denotes 2013), which could be a result of poor intracellular accumulation within astrocytes.
T1375 110219-110413 Sentence denotes In vitro studies have demonstrated darunavir and raltegravir intracellular concentrations to be approximately 100-fold lower (with higher EC50 values) in microglia than in PBMCs (Asahchop et al.
T1376 110414-110420 Sentence denotes 2017).
T1377 110421-110591 Sentence denotes Another study measured intracellular concentrations of dolutegravir, tenofovir and emtricitabine in primary human astrocytes, microglia, pericytes and BMECs (Patel et al.
T1378 110592-110598 Sentence denotes 2019).
T1379 110599-110712 Sentence denotes Intracellular ARV concentrations were typically significantly higher in BMECs than in the other brain cell types.
T1380 110713-110847 Sentence denotes Dolutegravir achieved the highest relative concentrations within each cell type, whereas tenofovir accumulated the least (Patel et al.
T1381 110848-110854 Sentence denotes 2019).
T1382 110855-111004 Sentence denotes Furthermore, 24 h treatment with morphine significantly decreased intracellular accumulation of composite ARV concentrations, but only in astrocytes.
T1383 111005-111124 Sentence denotes In contrast, morphine exposure significantly increased the net accumulation of drugs within BMECs compared to controls.
T1384 111125-111194 Sentence denotes BMECs may sequester ARV drugs as a protective mechanism (Patel et al.
T1385 111195-111201 Sentence denotes 2019).
T1386 111202-111480 Sentence denotes Using experimental data from SIV-infected, morphine-addicted macaques, mathematical modeling suggests that morphine exposure increases the proportion of cells with high susceptibility to SIV infection, at least in part, because of increased co-receptor expression (Vaidya et al.
T1387 111481-111487 Sentence denotes 2016).
T1388 111488-111754 Sentence denotes In addition to promoting a higher steady state viral loads and larger CD4 count declines, the model also predicts that morphine exposure results in the need for more efficacious ARV treatment than would be necessary for animals not exposed to morphine (Vaidya et al.
T1389 111755-111761 Sentence denotes 2016).
T1390 111762-111927 Sentence denotes Although the direct impact of morphine on ARV concentrations was not investigated, the study provides evidence supporting morphine’s negative impact on ARV efficacy.
T1391 111929-111945 Sentence denotes Publisher’s Note
T1392 111946-112064 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T1393 112066-112082 Sentence denotes Acknowledgements
T1394 112083-112318 Sentence denotes Portions of this review were initially presented at the Satellite Symposium of the 25th SNIP Scientific Conference entitled, “Unraveling NeuroAIDS in the Presence of Substance Use Disorder” that was sponsored and organized by NIH/NIDA.
T1395 112319-112329 Sentence denotes Co-Chairs:
T1396 112330-112380 Sentence denotes Yu (Woody) Lin and Roger Sorensen (April 10, 2019)
T1397 112382-112389 Sentence denotes Funding
T1398 112390-112576 Sentence denotes This work was supported by the National Institute on Drug Abuse: R01 DA034231 (KFH), R01 DA044855 (KFH), R01 DA045588 (KFH), R01 DA018633 (KFH), R21 DA045630 (MM), and R01 DA045596 (SF).
T1399 112578-112611 Sentence denotes Compliance with Ethical Standards
T1400 112613-112633 Sentence denotes Conflict of Interest
T1401 112634-112693 Sentence denotes The authors declare that they have no conflict of interest.