Camilo-Contreras, A. | Search bioRxiv

bioRxiv2026

Antigen Stimulation Reactivates HIV-1 Proviruses Despite Integration in Repressive Chromatin

Intact HIV-1 proviruses become progressively enriched in transcriptionally repressive genomic regions during long-term antiretroviral therapy (ART) and in elite controllers, raising questions about their capacity for reactivation in vivo. We used an antigen-restricted quantitative viral outgrowth assay (ag qVOA) to test whether cognate antigen stimulation can reverse latency of proviruses integrated within repressive chromatin. Using cells from two people with HIV (PWH) on ART, one on long-term treatment and one an elite controller, we show that antigen-specific stimulation induces viral outgrowth from intact proviruses integrated into a pericentromeric transition region and a zinc finger gene, respectively. These findings demonstrate that antigen recognition can overcome epigenetic constraints to reactivate proviruses with low inducibility and suggest that proviruses in so-called "deeper latency" may contribute to residual viremia and viral rebound following treatment interruption.

immunology↗

bioRxiv2025

Proviruses in CD4+ T cells reactive to autologous antigens contribute to nonsuppressible HIV-1 viremia

Antiretroviral therapy (ART) halts HIV-1 replication, reducing plasma virus levels to below the limit of detection, but it is not curative due to a reservoir of latently infected CD4+ T cells. In some people living with HIV-1 (PLWH), plasma HIV-1 RNA becomes persistently detectable despite optimal ART. This nonsuppressible viremia (NSV) is characterized by identical, non-evolving HIV-1 RNA variants expressed from infected CD4+ T cell clones. The mechanisms driving persistent virus production from a specific population of infected cells are poorly understood. We hypothesized that proviruses in cells responding to chronic immunologic stimuli, including self-associated antigens, may drive viral gene expression and NSV. Here, we demonstrate that stimulation of CD4+ T cells with autologous cell lysates induces virus production in an MHC-II-dependent manner. In 7 of 8 participants with NSV, we recovered viral RNA released ex vivo in response to autologous cell lysates that matched plasma virus. This process involves both defective and replication-competent proviruses residing in conventional T cells, and is also observed in PLWH with undetectable viremia. These findings suggest that recognition of self-associated antigens is an important cause of HIV-1 reservoir expression, which can contribute to persistent systemic inflammation and potential rebound upon ART interruption. One sentence summaryHIV-1 viremia not suppressed by effective ART can be caused by proviruses in CD4+ T cells reactive to autologous antigens.

immunology↗