Table 2 Cellular and molecular interactions (in vitro)
Major effects HIV pathogena ARV Opioids Outcome Model system (in vitro) Citation(s)
Mixed-Glia
HIV expression HIV No • Dynorphin
• U50,488
(KOR agonists) • ↑ HIV-1 expression,
• Dynorphin (KOR agonist) ↑ TNF-α, IL-6 mRNA and protein Human fetal neural cells, HIV-infected promonocyte (U1) line (Chao et al. 1995)
HIVSF162 No • U50,488
• U69,593
• Dynorphin1–17;
(KOR agonists)
• Morphine • KOR agonists ± TNF-α differentially ↓ HIV p24 Human, primary mixed neurons and glia (Chao et al. 1998a)
Chemokines Tat1–86 No Morphine • ↑ CCL5, CCL2
• ↑ [Ca2+]i (Beclin1 dependent)
• ↓ Autophagy Mouse, primary mixed glia (Lapierre et al. 2018)
HIVSF162 (R5) No Morphine • ↑ HIV-1 Tat-induced LTR expression
• ↑ CCR5 expression (inhibited by bivalent ligand in astrocytes)
• ↑ IL-6
• ↑ CCL5 Human, primary mixed glia (El-Hage et al. 2013)
Glial restricted precursors: survival & MOR, DOR, KOR expression Tat1–72 No Morphine (acting via DOR and/or KOR) • ↑ Caspase-3 activation & ↑ cell death by Tat or morphine via DOR, KOR
• No opioid-Tat interactions Mouse, primary glial precursors (Buch et al. 2007)
MOR expression in NPCs;
NPC survival and developmental fate Tat1–72 No Morphine • MOR expressed by subsets of NPCs
• ↑ Astrocyte and immature glial death Mouse, primary mixed glia (Khurdayan et al. 2004)
MOR and CCR5 interactions Tat1–86 (from HIVIIIB) No Morphine • ↓ Neuronal survival via CCR5 activation in glia (rescued by BDNF treatment) Mouse, primary neurons and glia (Kim et al. 2018)
HIV infectivity MOR-CCR5 dimerization HIVSF162 (R5) No Morphine
CCR5-MOR bivalent ligand 1b • MOR-CCR5 bivalent ligand blocks HIV infection in astroglia, but not microglia, with morphine
• MOR-CCR5 bivalent ligand blocks the fusion of HIV gp160 and CCR5-CD4-expressing HEK cells Human, primary astrocytes and microglia; HEK-293T cells (Yuan et al. 2013; Arnatt et al. 2016)
HIV expression and maturational fate of neurons and astroglia HIVBaL (R5) No Morphine • ↑ HIV p24 and ↑ Tat mRNA levels with morphine after 21 days
• ↓ Proliferation of neural progenitors; ↑ astroglial and ↑ neuronal differentiation Human, neural progenitors (Balinang et al. 2017)
Astrocytes
HIV expression HIVSF162 (R5) No Morphine • ↑ HIV p24
• ↑ CCL2 Human, primary astrocytes (Rodriguez et al. 2017)
Toll-like receptor (TLR) expression/function • Tat1–72
• gp120 No Morphine • ↑ TLR2 with Tat, Tat + morphine, gp120
• ↓ TLR9 with Tat, morphine, gp120 Mouse, primary astrocytes (El-Hage et al. 2011a)
Chemokines Tat1–72 No Morphine • ↑ CCL5, CCL2
• ↑ IL-6
• ↑ [Ca2+]i Mouse, primary astrocytes (El-Hage et al. 2005)
Tat1–72 No Morphine • ↑ CCL2
• ↑ CCL5
• ↑ Microglial migration Mouse, primary astrocytes (El-Hage et al. 2006a)
Tat1–72 No Morphine • ↑ CCL2, ↑ IL-6, ↑ TNF-α
• ↑ [Ca2+]i
• ↑ NF-κB trafficking and transcription
• No interaction / acceleration with morphine Mouse, primary astrocytes (El-Hage et al. 2008b)
Tat No • U50,488 (KOR agonist)
• Nor-BNI (KOR antagonist) • U50,488 ↓ CCL2
• U50,488 ↓ NF-κB Human, primary astrocytes (Sheng et al. 2003)
N/A No Morphine • ↑ CCR5, CCR3, CXCR2
• ↓ IL-8, CCL4 Human, astrocytoma U87 cell line, primary astrocytes (Mahajan et al. 2002)
• Tat1–86
• gp120IIIB No Morphine Regional differences in cytokine and ROS production —differed for each insult Mouse, primary astrocytes (Fitting et al. 2010a)
Oxidative stress / damage Tat1–72 No • DPDPE
• SNC-80
(DOR agonists) DOR agonists ↓ Tat-induced oxidative stress Human derived brain cell line (SK-N-SH) (Wallace et al. 2006)
Inflammation, maturation /plasticity • Tat86
• Tat101 No Morphine ↓ β-catenin signaling and variably decreases TrkB, BDNF, and NLRP1 mRNA in fetal astrocytes b Human, U87MG and fetal astrocytes (Chen et al. 2020)
Microglia
HIV replication HIVSF162 (R5) No • Endomorphin-1
• Endomorphin-2
(MOR agonists) • ↑ HIV p24 with endomorphin-1, but not endomorphin-2
• Endomorphin-1 acts via MOR, but not DOR / KOR Human, primary microglia (Peterson et al. 1999)
HIVSF162 (R5) No Morphine ↑ HIV p24 Human, primary microglia (El-Hage et al. 2014)
HIVSF162 (R5) No • U50,488; U69,593 (KOR agonists)
• Dynorphin Al-13 ↓ HIV p24 Human, primary microglia (Chao et al. 1996b)
• HIVJR-FL (R5)
• gp120 No β-endorphin • ↑ HIV expression
• ↑ HIV p24 (14-day post infection)
• gp120 ↑ IL-1, TNF, IL-6 Human, fetal microglia (Sundar et al. 1995)
HIVSF162 No • 8-CAC, U50,488 (KOR agonists)
• Cocaine • KOR agonist ↓ p24; blocked by KOR antagonists
• KOR agonist negates cocaine-induced ↑ HIV Human, fetal brain microglia (Gekker et al. 2004)
HIVSF162 No OPRL1 antisense
Nociceptin / orphanin FQ (OPRL1 agonist) • OPRL1 antisense (and sense) ↓ p24
• Nociceptin, no effect on p24 Human, fetal brain microglia and mixed neurons/glia (Chao et al. 1998b)
HIV expression • HIVSF162
• Tat ZDV U50,488 (KOR agonist) • ↓ p24 on day 14 with U50,488
• ↓ Neurotoxicity (U50,488)
• ↓ Quinolinate by microglia Human, fetal microglia and neural cells (Chao et al. 2000)
Chemokines and Cytokines Tat1–72 No Morphine • ↑ CCR5
• ↑ CD11b, ↑ CD40
• ↑ TNF-α, ↑ IL-6, ↑ IP-10
• ↑ iNOS Mouse, BV-2 and primary microglia (Bokhari et al. 2009)
MOR signaling Tat1–72 No Morphine • ↑ MOR (intracellular)
• ↑ MOR mRNA Mouse, N9 and primary microglia (Turchan-Cholewo et al. 2008)
Oxidative Stress Tat1–72 No Morphine • ↑ ROS [O2− (DHE), ↑ HO2•, H2O2 (DCF)]
• ↑ Protein carbonyls Mouse, N9 and primary microglia (Turchan-Cholewo et al. 2009)
Glutamate release Tat1–72 No Morphine ↑ Glutamate release via ↑ xc− cystine-glutamate antiporter expression/function Mouse, primary microglia (Gupta et al. 2010)
Neurons
HIV expression HIV No Morphine ↑ HIV expression Human derived, SH-SY5Y neuroblastoma cells (Squinto et al. 1990)
Homeostasis and Injury Tat1–86 No Morphine • ↑ [Ca2+]i,
• ↑ [Na+]i
• ↓ ΔΨm (mitochondrial) instability
• ↑ Dendritic degeneration Mouse, primary neurons (Fitting et al. 2014a)
Mitochondrial inner membrane potential and ROS • Tat1–86, Tat1–72
• gp120 No Morphine ↑ ΔΨm instability and oxidative stress ↑ with Tat + morphine, ↑ neuroprotection with allopregnanolone Human, primary neurons ; mouse, striatal medium spiny neurons; mouse, striatal medium spiny neurons, SH-SY5Y neuroblastoma cells (Turchan-Cholewo et al. 2006; Paris et al. 2020)
Neuronal survival Tat1–86 No Morphine • ↓ Neuronal survival from Tat + morphine and ↓ glial CX3CL1 rescued by CX3CL
• CX3CL1 (fractalkine) regulates microglial motility Mouse, primary neurons and mixed glia (Suzuki et al. 2011)
Tat1–86 No Morphine • ↓ Proliferation
• ↑ ERK1/2 activation
• ↑ p53 and p21
• ↓ Cyclin D1 and Akt levels Human, neuronal precursors (Malik et al. 2014)
Tat1–72, Tat1–86 No Morphine • ↓ Neuronal survival
• ↑ Neuronal survival with ibudilast (AV411) (inhibiting glial NF-κB blocks Tat ± morphine neurotoxicity) Mouse, primary neurons and mixed glia (Gurwell et al. 2001; El-Hage et al. 2014)
White matter/oligodendroglial pathology
Changes in OL survival and morphology Tat1–86 No Morphine (25 mg pellet, 7 days); morphine (in vitro) • ↑ Degeneration of OLs
• ↑ TUNEL reactivity
• ↑ Caspase-3 activation Mouse, Tat tg; primary OLs (Hauser et al. 2009)
Blood-brain barrier and the neurovascular unit
BBB model integrity and function Tat1–86 No Morphine • ↑ TNF-α
• ↑ IL-8
• ↓TEER
• ↑ JAM-2 expression
• ↑ Monocyte transmigration with CCL5 Human, using primary BMVEC and primary astrocytes (Mahajan et al. 2008)
ARV accumulation Tat1–86 DTG
FTC
TFV Morphine • ↓ Intracellular ARV concentrations Human, primary astrocytes (Patel et al. 2019)
HIV-1 strain differences
Neuronal Survival Tat1–86 (clades B & C) No Morphine • ↓ Neuronal survival via MOR on mixed glia
• ↑ ROS in astrocytes
• ↑ Iba1 and 3-NT microglia with morphine Mouse, primary neurons and mixed glia (Zou et al. 2011)
• gp120IIIB
• gp120MN (X4)
• gp120ADA (R5) No Morphine ↓ Neuronal survival in presence of glia with gp120MN and transiently with gp120IIIB (X4), not R5-tropic gp120, in combination with morphine Mouse, primary neurons and mixed glia (Podhaizer et al. 2012)
Proliferation and maturational fate of neural progenitors and oligodendroglia • HIVSF162 (R5)
• HIVIIIB (X4) No Morphine • ↓ Proliferation of immature neural and OL progenitors with Tat + morphine
• ↓ NPC DNA synthesis with R5-tropic HIV + morphine
• ↑ NPC DNA synthesis with X4-tropic HIV + morphine Mouse, Tat tg; Mouse, Human, primary neural progenitors (Hahn et al. 2012)
GABA function • HIVBaL (R5)
• gp120 (ADA, MN, and IIIB)
• Tat1–86 No Morphine • Tat or morphine ↓ KCC2 levels via CCR5
• ↑ KCC2 prevents Tat and R5 HIV, gp120, but not X4, gp120 neurotoxicity ± morphine Human, primary neurons, hNPCs (Barbour et al. 2020)
Astroglial CCL5 and neuroprotection • gp120IIIB (X4)
• gp120BaL (R5) No • Morphine (10 μM)
• DAMGO • Morphine ↑ astroglial CCL5 blocking gp120BaL neurotoxicity
• Morphine (or CXCL12) does not block gp120IIIB neurotoxicity Rat, mixed neurons and glia; isolated neurons, astrocytes and microglia (Avdoshina et al. 2010)
aassumed Clade B, unless noted otherwise, b statistical findings for some results are unclear
ARV, antiretroviral(s); BMVEC, brain vascular endothelial cells; [Ca2+]i intracellular calcium concentration; 8-CAC, 8-carboxamidocyclazocine; DAMGO, D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DCF, dihydro-dichlorofluorescein; DOR, δ-opioid receptor; DHE, dihydroethidium; DTG, dolutegravir; DPDPE, [D-Pen2,D-Pen5]enkephalin; FTC, emtricitabine; GABA, γ-aminobutyric acid; Iba1, ionized calcium-binding adapter molecule 1; JAM-1, junctional adhesion molecule-1; KCC2, K+-Cl− cotransporter 2; KOR, κ-opioid receptor; LTR, long terminal repeat; ΔΨm, mitochondrial inner membrane potential; MOR, μ-opioid receptor; [Na+]i, intracellular sodium concentration; nor-BNI, nor-binaltorphimine; NPCs, neural progenitor cells; OLs, oligodendroglia; ROS, reactive oxygen species; TEER, transendothelial electrical resistance; TFV, tenofovir; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; ZDV, zidovudine
For practicality, the table is 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 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)