Methaneseleninic acid, a circadian-modulating agent, reactivates latent HIV-1 infection without cellular activation or proliferation

Human immunodeficiency virus (HIV)-1 transcriptional activity is under circadian control in virally suppressed people with HIV (PWH), and circadian transcription factors can positively affect HIV transcription <i>in vitro</i>. We aimed to determine whether pharmacologic modulation of cell-autonomous circadian cycles can reverse HIV latency. We examined the effects of a known circadian modulator, the organic selenium compound, methaneseleninic acid (MSA), on viral reactivation, and cellular activation and proliferation in near-full-length latently infected cell lines and primary peripheral blood CD4+ T cells from virally suppressed males with HIV. MSA robustly reactivated HIV in latently infected cell lines and induced an increase in cell-associated unspliced but not multiply spliced HIV RNA in primary CD4+ T cells without cellular activation, proliferation, or changes in HIV DNA. Bulk RNA sequencing of primary CD4+ T cells from people with HIV indicated MSA alters gene expression favoring apoptosis. This work promisingly demonstrates a novel target to reactivate latent HIV.IMPORTANCEThis study explores a novel and promising approach to tackle HIV latency, a major barrier to curing HIV infection. Despite effective antiretroviral therapy, HIV can persist in a dormant state within certain cells, forming a reservoir that is challenging to eliminate. This research investigates the potential of modulating the body's internal circadian rhythms, which regulate many biological processes, as a means to reactivate and purge this latent HIV reservoir. Specifically, it was found that a circadian-modulating compound called methaneseleninic acid could robustly reactivate latent HIV in infected cell lines and primary cells from people with HIV, without causing broader cellular activation or proliferation. This targeted reactivation of latent HIV by manipulating circadian cycles represents a unique and intriguing strategy that could potentially contribute to future HIV cure efforts.