Chronic morphine administration differentially modulates viral reservoirs in SIVmac251 infected rhesus macaque model

Abstract

HIV persists in cellular reservoirs despite effective anti-retroviral therapy with rebound of viremia upon therapy interruption. Opioids modulate the immune system and suppress antiviral gene responses, which significantly impact people living with HIV (PLWH). However, the effects of opioids on viral reservoir remains elusive. Herein, we describe a morphine dependent SIVmac251 infected Rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. RMs were ramped up with morphine (n=10) or saline (n=9) for two weeks to a final dosage of 5mg/kg administered twice daily, which was maintained for seven weeks, and then infected with SIVmac251. Combined anti-retroviral therapy (cART) was initiated in approximately half the animals in each group five weeks post-infection and morphine/saline administration continued for 10 months. Among drug naïve macaques, there were no differences in plasma/CSF viral load nor in cell-associated DNA/RNA loads. However, within the cART-suppressed macaques, there was a reduction in cell-associated DNA load, intact proviral DNA copy numbers, and inducible SIV reservoir in both peripheral blood and lymph nodes (LNs) of morphine-administered RMs compared to saline controls. Further, PBMCs of morphine administered RMs, a reduction in Th1 polarized CD4+ T cells and in LNs there was a reduction in the total Tfh and Th1 like Tfh cells were observed, indicating probably have impact on reduction of viral reservoirs. In distinction to PBMC and LNs, within the CNS size of latent SIV reservoirs was higher in the CD11b+ microglia/macrophages of morphine-dependent RMs. These data suggest that morphine plays a role in modulating SIV reservoirs, reduces the CD4+ T-cell reservoir in both peripheral blood and LNs, and increases microglia/macrophage reservoirs in CNS. These findings will aid in understanding of molecular mechanism(s) of opioid-mediated differential modulation of viral reservoirs and evaluation of therapeutic strategies to reduce/eliminate HIV reservoirs in opioid-dependent PLWH.Author summaryOpioids are commonly used as well as abused by HIV infected individuals, are known to suppress immune responses. However, their effects on modulating viral reservoir dynamics is not known. Here we developed a morphine dependent SIVmac251 infected rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs and immune cells. We found that there was no difference in viral loads or cell-associated DNA/RNA loads among morphine dependent vs. saline treated control macaques. On the other hand, when macaques were treated with cART, there was a reduction in SIV reservoirs both in periphery and lymphoid tissues in morphine administered RMs, and the size of latent SIV reservoir was higher in the CNS CD11b+ microglia/macrophages as compared to control macaques. Therefore, these new data form macaque models suggest that PLWH who suffering from opioid use disorders have higher reservoirs in CNS as compared to lymphoid system. Thus, through understanding these reservoirs among PLWH who uses opioids are critical for better designing HIV cure strategies.

Deprenyl reduces inflammation during acute SIV infection

“…SIV RNA in the plasma was quantified by using quantitative reverse transcription-PCR (qRT-PCR) using our established protocols ( Acharya et al., 2020 ). Plasma was separated from blood samples collected in K2-EDTA vacutainer tubes (Becton Dickinson, San Diego, CA) within 4 h of collection.…”

Chronic Morphine Exposure distorts Gut-Brain Interrelationships in SHIV Infected Rhesus Macaques

“…The normalization for the conserved RPP30 gene was done to yield equivalent copies of SIV gag per million cells. Also, viral RNA levels were estimated using quantitative PCR (qPCR) assays as previously described (33).…”

“…This is followed by increased tissue damage/ neurodegeneration, and augmented IL-1β-and TNF-α-dependent HIV reactivation within microglia (30)(31)(32). Our laboratory has recently shown that following cART-mediated viral suppression, morphine-dependent SIV-infected rhesus macaques harbored elevated replicationcompetent reservoirs in the brain myeloid cells (33).…”

The Contributions of Clinical Pharmacology to HIV Cure Research

“…Although memory CD4+ T cells represent the principal component of latent viral reservoirs, more specific markers are needed to identify memory subsets enriched for replication‐competent HIV reservoirs 9 . In addition to CD4+ T cells, the myeloid lineage of cells, including microglia and perivascular macrophages in the brain and urethral tissue macrophages, also serve as viral reservoirs 10 . These same anatomic sites may also be pharmacologic sanctuaries, as evidenced by concentrations of antiretroviral (ARV) drugs lower than those in peripheral blood and, in some cases, associated with evidence for low‐level ongoing virus replication 11,12 …”