Opioid use does not limit potent low-dose HIV-1 latency reversal agent boosting

The combined effects of the HIV-1 and opioid epidemics on virus reservoir dynamics are less well characterized. To assess the impact of opioid use on HIV-1 latency reversal, we studied forty-seven suppressed participants with HIV-1 and observed that lower concentrations of combination latency reversal agents (LRA) led to synergistic virus reactivation ex vivo, regardless of opioid use. The use of a Smac mimetic or low-dose protein kinase C agonist, compounds that did not reverse latency alone, in combination with low-dose histone deacetylase inhibitors generated significantly more HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin, the maximal known HIV-1 reactivator. This LRA boosting did not differ by sex or race and associated with greater histone acetylation in CD4+ T cells and modulation of T cell phenotype. Virion production and the frequency of multiply spliced HIV-1 transcripts did not increase, suggesting a post-transcriptional block still limits potent HIV-1 LRA boosting. ### Competing Interest Statement Athe Tsibris has received remuneration or lab funding from Gilead Sciences, Merck & Co, and EBSCO-Dynamed. Nina Lin is an employee of Moderna, Inc. ### Funding Statement This work is supported by the NIH R61 DA047038 and R33 DA047038 and was facilitated by the Providence/Boston CFAR (P30AI042853) and the Harvard University CFAR (P30AI060354. The project was further supported by Clinical Translational Science Award 1UL1TR002541. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was reviewed and approved by the Institutional review board at Boston Medical Center and the Massachusetts General Brigham Human Research Committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors