Table 1 Clinical and preclinical findings
Major effects HIV pathogena ARV Opioids Outcome Model system Citation(s)
Clinical findings (human)
HIV progression and/or ARV adherence HIV cART • SUD
• Prescription opioids for pain • ↑ Viral load with SUD
• ↓ ARV adherence
• ↑ Frequency of prescription drugs with pain + SUD Human (Denis et al. 2019)
HIV cART OUD • ↓ Lasting viral suppression
• ↓ Adherence to cART for 3 years Human (Lemons et al. 2019)
HIV ARV naive Injection drug use ↓ CD4 counts Human (Meijerink et al. 2014)
HIV encephalitis (HIVE)
HIV infection CNS HIV ZDV Former drug use (+ OST) • ↑ Multinucleated giant cells
• ↑ HIV p24 Human, postmortem brain (Bell et al. 1998)
Microglial activation HIV • ARV
• ZDV OUD ↑ CD68 microglial activation only in non-OUD HIV+ PWH Human, postmortem brain (Smith et al. 2014)
HIV • ARV
• ZDV, other monotherapies Injection drug use (+ OST) ↑ Microglial activation Human (Bell et al. 2002)
HIV No info Drug use • ↑ MHC class II
• ↑ CD68 Human, postmortem brain (Anthony et al. 2005)
HIV No info OUD (44% methadone, 36% other opiates) • ↓ CD68, HLA-D in HIV and HIVE with OUD
• No effect of IDU on CD68 Human, postmortem brain (Byrd et al. 2012)
Plasma cytokines HIV cART OUD (codeine, fentanyl, morphine) ↑ sTNF-R2, not sCD14, TNF-α, sTNF-R1, in plasma Human (Ryan et al. 2004)
HIV ARV naive Reported heroin use • ↓ MIP-1α, MIP-1β, MCP-2 in blood after stimulation with LPS
• ↑ CCR5 expression in CD4 cells Human (Meijerink et al. 2015)
HIVE HIV No info OUD • ↑ Parenchymal inflammatory infiltrates
• ↑ HIV PCR amplification products Human, postmortem brain (Gosztonyi et al. 1993)
Aberrant immune responses HIV No info SUD (opioids, alcohol, marijuana, cocaine) (+ OST) • ↑ Autoantibodies and delayed hypersensitivity to neural antigens OUD only
• No HIV effect/interaction Human (Jankovic et al. 1991)
Learning-memory HIV 50-70% on cART Heroin, crack/cocaine • ↓ Total learning; ↓ Learning slope
• ↓ Delayed recall Human, female (Meyer et al. 2013)
HIV cART Reported heroin use • ↓ Recall memory
• ↓ Working memory Human (Byrd et al. 2011)
HIV No info SUD (opioids, alcohol, marijuana, cocaine) • ↓ Complex figure copy
• ↓ Delayed recall Human (Concha et al. 1997)
Neuropsychological performance cART OST (methadone) No effect of OST Human (Applebaum et al. 2010)
Cognitive function HIV cART OUD • ↓ Cognitive performance with anticholinergics, but not opioids, anxiolytics, or anticonvulsants Human (Rubin et al. 2018)
Memory
Cognitive function HIV cART SUD (alcohol, cocaine, heroin) • ↓ Working memory in HIV+
• ↓ Spatial and verbal response times in women, irrespective of HIV status
• ↑ Response time with cocaine use Human (Martin et al. 2018)
Visual and cognitive function HIV No info OUD (+ OST, methadone) • ↑ Pattern-shift visual evoked potential delay with methadone
• No HIV effect/interaction Human (Bauer 1998)
Transmission risk HIV No info OST ↓ Frequency of injection drug use Human (Kwiatkowski and Booth 2001)
HIV cART OST • ↓ Frequency of heroin injection
• ↑ On ARV Human (Pettes et al. 2010)
Motor and visual function HIV No info OST • ↓ Digital Finger-Tapping test
• ↓ Visual motor pursuit Human (Silberstein et al. 1993)
ARV adherence HIV cART OST • ↑ ARV adherence in PWH with OST vs. OUD Human (Mazhnaya et al. 2018)
PENK expression HIV Pre- and post-cART SUD • ↓ PENK in HIVE vs. HIV−
• ↓ DRD2L HIV+ vs. HIVE & HIV−
• ↓ DRD2L correlates with
↑ cognitive performance Human, post mortem brain (Gelman et al. 2012)
OPRM1 polymorphisms, splice variants HIV No info SUD C17T MOR polymorphism correlates with ↑ risk of cocaine, alcohol & tobacco (but not opiate) use Human (Crystal et al. 2012)
HIV cART No Some OPRM1 polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2012)
HIV No info MOR-1K expression • ↑ MOR-1K in HIVE
• ↑ CCL2, CCL6, CCL5, but not CXCR4, CCR5 or CD4 receptor in HIVE Human, postmortem brain (Dever et al. 2014)
OPRK and PDYN polymorphisms HIV cART No Some OPRK and PDYN polymorphisms may alter HIV severity / response to ARV Human (Proudnikov et al. 2013)
Sensory Neuropathy HIV cART SUD HIV sensory neuropathy- regardless of SUD (trends, not significant) Human (Robinson-Papp et al. 2010)
Preclinical in vivo findings (animal)
HIV entry into the brain Mixture of SIV17-EFr, SHIVKU_1B, SHIV89.6P No Morphine (5 mg/kg i.m., b.i.d., ≤ 56 weeks) • ↑ CSF viral load
• ↑ Viral migration through BBB for SHIVKU Rhesus macaques (Kumar et al. 2006)
SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d.) • ↑ CD4+ and CD8+ T cells
• ↑ CSF viral load
• ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al. 2011).
Viral load and HIV progression Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine (5 mg/kg, i.m., t.i.d., 20 weeks) • ↑ Viral load; ↓ CD4 counts
• ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al. 2007; Perez-Casanova et al. 2008)
SIV gene mutation/evolutiontat Mixture of SIV17-EFr, SHIVKU _1B, SHIV89.6P No Morphine
(5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts
• tat evolution—inverse correlation with SIV progression
• ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006; Noel et al. 2006b)
nef • ↑ Viral load; ↓ CD4 counts
• ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al. 2006a)
env • ↑ Viral load; ↓ CD4 counts
• ↑ env evolution (V4 region) correlates with SIV progression + morphine
• ↑ env evolution in CSF with morphine (Rivera-Amill et al. 2007, 2010b)
vpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality
• ↓ vpr evolution with morphine (Noel and Kumar 2007; Rivera et al. 2013)
Neuronal injury, survival, oxidative stress gp120 HIV-1LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal
• ↓ PSD95 during chronic and withdrawal
• ↑ Sphingomyelin
• ↓ Ceramide Mouse, gp120 tgb (Bandaru et al. 2011)
HIV No Morphine (37.5 mg s.c, 5 days) ↓ neuron survival HIV tg + morphine Rat, HIV-1 tg, female (Guo et al. 2012)
SIV
HIV Tat No Morphine (3 mg/kg i.m., q.i.d., 3 weeks) • ↑ miR-29b, ↓ PDGF-B mRNA, ↑ PDGF-BB with morphine and SIV
• ↓ PDGF-B, ↓ neuron survival with CM from morphine-treated astrocytes Rhesus macaques; Ratb, primary neurons, astrocytes (Hu et al. 2012)
Synaptic transmission Tat1–86 No Morphine ex vivo (1 μM) to the bath ↓ mIPSC frequency Mouse, male and female, PFC slices, ex vivo (Xu and Fitting 2016)
SIVmacR71/17E
Tat No info • Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., 12 months)
• Morphine in vitro • SIV ↑ Synaptic protein HSPA5
• Tat ↑ HSPA5 mRNA (in vitro) Rhesus macaques;
Human,
SH-SY5Y neuroblastoma cells in vitro (Pendyala et al. 2015)
White matter effects SIVmacR71/17E No Morphine (3 mg/kg i.m., q.i.d., ≤ 59 weeks) • ↑ Focal, demyelinating lesions
• ↑ Macrophages in areas of myelin loss Rhesus macaques (Marcario et al. 2008),
CNS metabolites SIVsmm9 No info Morphine (escalating doses of 1–3 mg/kg i.m., q.i.d., ≤ 4 years) • ↑ Survival time
• ↑ Creatine in white matter (SIV + morphine only)
• ↑ Myo-inositol in putamen Rhesus macaques (Cloak et al. 2011)
Neuroinflammation Tat1–86 No Morphine (10 mg/kg i.p., b.i.d., 5 days) ↑ Iba1+ 3-NT+ microglia Mouse, Tat tg, males (Zou et al. 2011)
Chemokines Tat1–72
(25 μg intrastriatal injection) No Morphine (25 mg pellet, 5 days) • ↑ CCL2 in astrocytes is regulated by CCR5
• ↑ CCL2 in macrophages/microglia
• CCL2-knockout blocks morphine + Tat-induced glial reactivity Mouse (El-Hage et al. 2008a)
Cytokines, Chemokines HIV Tat (10 μg/kg i.v.) No Morphine (25, 75 mg pellet, 6 days) • Morphine ↑ death in Tat + bacterial infection
• ↑ TNFα, IL-6, CCL2,
• ↑ TLR2, TLR4, TLR9 Mouse, male, in vivo; microglia in vitro (Dutta et al. 2012)
MOR expression HIV-1IIIB gp120 (X4) No MOR ↑ MOR mRNA Rats, HIV-1 tg males (Chang et al. 2007)
MOR-coupling efficacy to G proteins Tat1–86 No • Morphine (acute, 10 mg/kg i.p.)
• 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)
Neuroinflammation; morphine tolerance (antinociception), physical withdrawal, reward Tat1–86 No Morphine (75 mg pellet, 5 days) • ↑ Tolerance (↓ anti-nociceptive potency and ↓ withdrawal symptoms)
• ↑ CPP and cytokines (24 h after withdrawal)
• Above effects reduced by CCR5 blockade Mouse, Tat tg, males (Gonek et al. 2018)
Neuropathy gp120 (0.2 μg), q.d. intrathecally No Morphine (3 μg, intrathecally, b.i.d., 5 days) • ↑ Mechanic allodynia
• ↑ Brd4 mRNA Rat, males, gp120 (Takahashi et al. 2018)
Morphine efficacy, potency Tat1–86 No Morphine (acute, 2–8 mg/kg s.c.) ↓ Antinociceptive potency and efficacy (tail flick) Mouse, Tat tg, males (Fitting et al. 2012)
Morphine tolerance, physical dependence Tat1–86 No Morphine (75 mg pellet, 4 days) • ↑ Antinociceptive tolerance
• ↓ Physical dependence Mouse, Tat tg, males (Fitting et al. 2016)
Locomotor function Tat1–86 No Oxycodone (0–10 mg/kg, i.p., 15 min prior behavioral assay) ↑ Locomotor activity, center entries (open field) Mouse, Tat tg, females (Salahuddin et al. 2020)
SIVmacR71/17E No Morphine (escalating doses of 1–2.5 mg/kg i.m., q.i.d., 59 weeks) ↓ Motor skill Rhesus macaques (Marcario et al. 2016)
Tat1–86 No Oxycodone (acute, 0.1–10 mg/kg, i.p.) ↑ Psychomotor effects Mouse, Tat tg, females (Paris et al. 2020)
BBB integrity Tat No Morphine (25 mg pellet, 5 days) ↑ Dextran extravasation across the blood-brain barrier Mouse, Tat tg females (Leibrand et al. 2019)
Immune cell trafficking into CNS Tat No Morphine • ↑ Infiltration of monocytes and T cells into S. pneumoniae-infected CNS with morphine
• ↑ T cell CXCR4 and CCR5 expression with morphine Mouse, CNS infection (S. pneumoniae), males (Dutta and Roy 2015)
ARV accumulation Tat DTG
ABC
3TC Morphine (2 mg/day, s.c.. osmotic pump, 5 days) ↓ Dolutegravir and abacavir, but no change in lamivudine in brains of morphine-treated animals Mouse, Tat tg females (Leibrand et al. 2019)
Circadian rhythms Tat1–86 No Morphine (25 mg pellet, last 5 days) ↓ Total wheel-running activity Mouse, Tat tg, males (Duncan et al. 2008)
aassumed Clade B, unless noted otherwise; b sex not reported; c authors reported a trend that was not significant
ABC, abacavir; ARV, antiretroviral(s); BBB, blood-brain barrier; b.i.d., twice a day; Brd4, Bromodomain-containing protein 4; CPu, caudate-putamen; CNS, central nervous system; CPP, conditioned place preference; CM, conditioned medium; CSF, cerebrospinal fluid; DAMGO [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DRD2L, type 2 dopamine receptor; DTG, dolutegravir; HIVE, HIV encephalitis (typically seen pre-cART); HSPA5, heat shock 70-kDa protein A 5; IDU, injection drug use; i.m., intramuscularly; i.p., intraperitoneal; Iba1, ionized calcium-binding adapter molecule 1; 3TC, lamivudine; MHC class II, major histocompatibility class II; mIPSC, miniature inhibitory postsynaptic currents; MOR, μ-opioid receptor; No info, information not provided or uncertain; OST, opioid substitution therapy; OUD, opioid use disorder; PFC, prefrontal cortex; PENK, preproenkephalin; q.d., once a day; q.i.d., four times a day; ROS, reactive oxygen species; s.c., subcutaneous; SUD, substance use disorder; tg, transgenic; t.i.d., three times a day; ZDV, zidovudine
For 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)