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)