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)