Virally Suppressed People Living with HIV Who Use Opioids Have Diminished Latency Reversal

Abstract

Of the 12 million people who inject drugs worldwide, 13% live with HIV. Whether opioid use impacts HIV pathogenesis and latency is an outstanding question. To gain insight into whether opioid use influences the proviral landscape and latent HIV reservoir, we performed intact proviral DNA assays (IPDA) on peripheral blood mononuclear cells (PBMCs) from antiretroviral therapy (ART)-suppressed people living with HIV (PWH) with or without current opioid use. No differences were observed between PWH with and without opioid use in the frequency of HIV intact and defective proviral genomes. To evaluate the latent reservoir, we activated PBMCs from ART-suppressed PWH with or without opioid use and assessed the induction of HIV RNA. PWH using opioids had diminished responses to ex vivo HIV reactivation, suggesting a smaller reversible reservoir of HIV-1 latently infected cells. However, in vitro studies using primary CD4+ T cells treated with morphine showed no effect of opioids on HIV-1 infection, replication or latency establishment. The discrepancy in our results from in vitro and clinical samples suggests that while opioids may not directly impact HIV replication, latency and reactivation in CD4+ T cells, opioid use may indirectly shape the HIV reservoir in vivo by modulating general immune functions.

HIV-1 latency reversal agent boosting is not limited by opioid use

“…Overall, participants were matched on the duration of ART and the duration of virus suppression, key variables that have been associated with HIV-1 reservoir size, 54 and our urine toxicology results were consistent with the participants' ascribed opioid use group. We found that opioid use generally did not impact LRA responsiveness, in contrast to a recent smaller study 41 . Our relatively large sample size allowed us to determine that this potency was less likely to be affected by sex, race, or ethnicity.…”

“…Here we found no effects of opioid use by indication, type, or pharmacology on markers of HIV-1 persistence. In the setting of persistently suppressed viremia, opioid use was less likely to modulate virus reservoir size, findings that agree with recent studies of injection heroin use (47, 63). Overall, participants were matched on the duration of ART and virus suppression, key variables that have been associated with HIV-1 reservoir size (64), and our urine toxicology results were consistent with the participants’ ascribed opioid use group.…”

“…Here we leveraged samples from forty-seven participants to confirm those findings, extend the observation to HDACi in combination with low-dose bryostatin more generally, and to LRA boosting with a Smac mimetic. A recent study identified that injection opioid use was associated with a lack of ex vivo HIV-1 activation to TCR agonism (47). and our findings in the subgroup of active injection opioid users agree with this.…”

“…The effects of buprenorphine, a partial µ opioid agonist and κ and δ opioid antagonist used in the treatment of opioid use disorder, on HIV-1 latency and its reversal have not been explored. A recent finding suggested that people with HIV who use opioids may have diminished responses to latency reversal 41 ; LRA efficacy in this burgeoning patient population is understudied.…”

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs

“…On the contrary, a recent ex vivo study using PBMCs from PWH on suppressive ART reported no differences in HIV intact and defective reservoir and reduced HIV-1 reactivation after stimulation through anti-CD3/CD28 beads in participants on opioids compared to those not on the drugs; this was correlated to repressed inflammatory cytokine responses (namely TNFα) [ 52 ]. However, the study had a limited sample size and high heterogeneity in the type and dose of opioids, as well as in the HIV-related characteristics of participants which may explain the discrepancy of these findings compared to other findings reported herein.…”