Abstract

Extracellular Condensates (ECs) are Endogenous Modulators of HIV Transcription and Latency Reactivation

Chioma Okeoma, Professor & Vice Chair of Research, New York Medical College

Persistence of latent HIV reservoir is the key challenge to HIV cure because the latent reservoir is not eliminated by ART and they serve as sources for viral rebound upon cessation of ART. Mechanisms that regulate HIV persistence are still unclear but emerging data highlight a possible role by extracellular condensates (ECs). In this study, we used model systems of post-integration latency to explore the role of ECs in reprogramming latent cells. We found that ECs from the brain of uninfected macaques (VEH) and SIV infected macaques (VEH|SIV) activate HIV transcription and that VEH and VEH|SIV ECs significantly increased expression of HIV antigen in latently infected cells. But the activation of HIV transcription, antigen expression, and latency reactivation was inhibited by ECs from the brain of THC-treated SIV infected macaques (THC|SIV). The virus produced by EC-reactivated latently infected cells potently infected other cells through cell-free and cell-cell mechanisms. The VEH|SIV ECs reversed dexamethasone-mediated inhibition of HIV transcription while TNFa-mediated reactivation of latency was reversed by THC|SIV. Transcriptome analysis showed substantial levels of altered host gene regulation, while Secretome analysis of HIV latently infected cells revealed that THC|SIV ECs increased secretion of Th2 cytokines and decreased secretion of proinflammatory cytokines. Overall, our findings support the hypothesis that ECs are endogenous host factors that regulate HIV persistence and provide evidence of the potential utility of THC ECs as useful latency promoting agents.