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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T70017","span":{"begin":1519,"end":1531},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T18180","span":{"begin":1682,"end":1688},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T79044","span":{"begin":1701,"end":1707},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T60696","span":{"begin":3523,"end":3539},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T35984","span":{"begin":3634,"end":3650},"obj":"http://purl.obolibrary.org/obo/GO_0002524"},{"id":"T69969","span":{"begin":3736,"end":3751},"obj":"http://purl.obolibrary.org/obo/GO_0007611"},{"id":"T74458","span":{"begin":3736,"end":3744},"obj":"http://purl.obolibrary.org/obo/GO_0007612"},{"id":"T70873","span":{"begin":3745,"end":3751},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T14119","span":{"begin":3803,"end":3811},"obj":"http://purl.obolibrary.org/obo/GO_0007612"},{"id":"T38670","span":{"begin":3815,"end":3823},"obj":"http://purl.obolibrary.org/obo/GO_0007612"},{"id":"T338","span":{"begin":3923,"end":3929},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T64140","span":{"begin":3942,"end":3948},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T84433","span":{"begin":4354,"end":4360},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T61490","span":{"begin":4432,"end":4438},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T75389","span":{"begin":5737,"end":5742},"obj":"http://purl.obolibrary.org/obo/GO_0038147"},{"id":"T57833","span":{"begin":7812,"end":7827},"obj":"http://purl.obolibrary.org/obo/GO_0043524"},{"id":"T93715","span":{"begin":8016,"end":8031},"obj":"http://purl.obolibrary.org/obo/GO_0043524"},{"id":"T1026","span":{"begin":8141,"end":8162},"obj":"http://purl.obolibrary.org/obo/GO_0007268"},{"id":"T99406","span":{"begin":11386,"end":11409},"obj":"http://purl.obolibrary.org/obo/GO_0050900"},{"id":"T43","span":{"begin":11534,"end":11539},"obj":"http://purl.obolibrary.org/obo/GO_0038147"},{"id":"T44","span":{"begin":11860,"end":11877},"obj":"http://purl.obolibrary.org/obo/GO_0007623"},{"id":"T45","span":{"begin":12295,"end":12323},"obj":"http://purl.obolibrary.org/obo/GO_1990708"}],"text":"Epidemiological studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T20","span":{"begin":204,"end":216},"obj":"Phenotype"},{"id":"T21","span":{"begin":588,"end":612},"obj":"Phenotype"},{"id":"T22","span":{"begin":680,"end":688},"obj":"Phenotype"},{"id":"T23","span":{"begin":1042,"end":1062},"obj":"Phenotype"},{"id":"T24","span":{"begin":2104,"end":2108},"obj":"Phenotype"},{"id":"T25","span":{"begin":2192,"end":2196},"obj":"Phenotype"},{"id":"T26","span":{"begin":2413,"end":2425},"obj":"Phenotype"},{"id":"T27","span":{"begin":3634,"end":3650},"obj":"Phenotype"},{"id":"T28","span":{"begin":5962,"end":5980},"obj":"Phenotype"},{"id":"T29","span":{"begin":5998,"end":6016},"obj":"Phenotype"},{"id":"T30","span":{"begin":7567,"end":7583},"obj":"Phenotype"},{"id":"T31","span":{"begin":8500,"end":8513},"obj":"Phenotype"},{"id":"T32","span":{"begin":8645,"end":8658},"obj":"Phenotype"},{"id":"T33","span":{"begin":10274,"end":10284},"obj":"Phenotype"},{"id":"T34","span":{"begin":10383,"end":10392},"obj":"Phenotype"},{"id":"T35","span":{"begin":11485,"end":11495},"obj":"Phenotype"},{"id":"T36","span":{"begin":11599,"end":11609},"obj":"Phenotype"},{"id":"T37","span":{"begin":12482,"end":12494},"obj":"Phenotype"},{"id":"T38","span":{"begin":12534,"end":12539},"obj":"Phenotype"}],"attributes":[{"id":"A20","pred":"hp_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/HP_0002383"},{"id":"A21","pred":"hp_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/HP_0031690"},{"id":"A22","pred":"hp_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/HP_0000726"},{"id":"A23","pred":"hp_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/HP_0100543"},{"id":"A24","pred":"hp_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/HP_0012531"},{"id":"A25","pred":"hp_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/HP_0012531"},{"id":"A26","pred":"hp_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/HP_0002383"},{"id":"A27","pred":"hp_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/HP_0041092"},{"id":"A28","pred":"hp_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/HP_0000763"},{"id":"A29","pred":"hp_id","subj":"T29","obj":"http://purl.obolibrary.org/obo/HP_0000763"},{"id":"A30","pred":"hp_id","subj":"T30","obj":"http://purl.obolibrary.org/obo/HP_0025464"},{"id":"A31","pred":"hp_id","subj":"T31","obj":"http://purl.obolibrary.org/obo/HP_0003006"},{"id":"A32","pred":"hp_id","subj":"T32","obj":"http://purl.obolibrary.org/obo/HP_0011096"},{"id":"A33","pred":"hp_id","subj":"T33","obj":"http://purl.obolibrary.org/obo/HP_0009830"},{"id":"A34","pred":"hp_id","subj":"T34","obj":"http://purl.obolibrary.org/obo/HP_0012533"},{"id":"A35","pred":"hp_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A36","pred":"hp_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A37","pred":"hp_id","subj":"T37","obj":"http://purl.obolibrary.org/obo/HP_0002383"},{"id":"A38","pred":"hp_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/HP_0031273"}],"text":"Epidemiological studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}

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studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014, 2015). In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998, 2002). 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. 2014). 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. 2000; McArthur et al. 2010; Saylor et al. 2016). 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. 2005; Bell et al. 2006; Anthony et al. 2008) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019). Opiate exposure in cART-treated PWH worsens CD4 counts and viral loads (Ryan et al. 2004), neuropathology (including increased tauopathy; Smith et al. 2014), CNS inflammation (Anthony et al. 2005, 2008; Smith et al. 2014), and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011). 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.\nTable 1 Clinical and preclinical findings\nMajor effects HIV pathogena ARV Opioids Outcome Model system Citation(s)\nClinical findings (human)\nHIV progression and/or ARV adherence HIV cART • SUD\n• Prescription opioids for pain • ↑ Viral load with SUD\n• ↓ ARV adherence\n• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)\nHIV cART OUD • ↓ Lasting viral suppression\n• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)\nHIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)\nHIV encephalitis (HIVE)\nHIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells\n• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)\nMicroglial activation HIV • ARV\n• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)\nHIV • ARV\n• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)\nHIV No info Drug use • ↑ MHC class II\n• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)\nHIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD\n• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)\nPlasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)\nHIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS\n• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)\nHIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates\n• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)\nAberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only\n• No HIV effect/interaction Human (Jankovic et al. 1991)\nLearning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope\n• ↓ Delayed recall Human, female (Meyer et al. 2013)\nHIV cART Reported heroin use • ↓ Recall memory\n• ↓ Working memory Human (Byrd et al. 2011)\nHIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy\n• ↓ Delayed recall Human (Concha et al. 1997)\nNeuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)\nCognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)\nMemory\nCognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+\n• ↓ Spatial and verbal response times in women, irrespective of HIV status\n• ↑ Response time with cocaine use Human (Martin et al. 2018)\nVisual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone\n• No HIV effect/interaction Human (Bauer 1998)\nTransmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)\nHIV cART OST • ↓ Frequency of heroin injection\n• ↑ On ARV Human (Pettes et al. 2010)\nMotor and visual function HIV No info OST • ↓ Digital Finger-Tapping test\n• ↓ Visual motor pursuit Human (Silberstein et al. 1993)\nARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)\nPENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−\n• ↓ DRD2L HIV+ vs. HIVE \u0026 HIV−\n• ↓ DRD2L correlates with\n↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)\nOPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol \u0026 tobacco (but not opiate) use Human (Crystal et al. 2012)\nHIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)\nHIV No info MOR-1K expression • ↑ MOR-1K in HIVE\n• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)\nOPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)\nSensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)\nPreclinical in vivo findings (animal)\nHIV 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\n• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)\nSIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells\n• ↑ CSF viral load\n• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).\nViral 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\n• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)\nSIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine\n(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts\n• tat evolution—inverse correlation with SIV progression\n• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)\nnef • ↑ Viral load; ↓ CD4 counts\n• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)\nenv • ↑ Viral load; ↓ CD4 counts\n• ↑ env evolution (V4 region) correlates with SIV progression + morphine\n• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)\nvpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality\n• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)\nNeuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal\n• ↓ PSD95 during chronic and withdrawal\n• ↑ Sphingomyelin\n• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)\nHIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)\nSIV\nHIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV\n• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)\nSynaptic 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)\nSIVmacR71/17E\nTat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)\n• Morphine in vitro • SIV ↑ Synaptic protein HSPA5\n• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;\nHuman,\nSH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)\nWhite matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions\n• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),\nCNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time\n• ↑ Creatine in white matter (SIV + morphine only)\n• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)\nNeuroinflammation 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. 2011)\nChemokines Tat1–72\n(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5\n• ↑ CCL2 in macrophages/microglia\n• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)\nCytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection\n• ↑ TNFα, IL-6, CCL2,\n• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)\nMOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)\nMOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)\n• 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. 2016)\nNeuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)\n• ↑ CPP and cytokines (24 h after withdrawal)\n• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)\nNeuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia\n• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)\nMorphine 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. 2012)\nMorphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance\n• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)\nLocomotor 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. 2020)\nSIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)\nTat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)\nBBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)\nImmune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine\n• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)\nARV accumulation Tat DTG\nABC\n3TC 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. 2019)\nCircadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)\naassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant\nABC, 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\nFor practicality, Tables 1 and 2 are limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes. 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)"}