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

Antiretroviral therapy (ART) halts human immunodeficiency virus–1 (HIV-1) replication, reducing plasma virus concentrations to below the limit of detection, but it is not curative because of 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, nonevolving 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 induced virus production in a major histocompatibility complex class II–dependent manner. In seven of eight participants with NSV, we recovered viral RNA released ex vivo in response to autologous cell lysates that matched plasma virus. This process involved both defective and replication-competent proviruses residing in conventional CD4⁺ T cells and was also observed in PLWH with undetectable viremia. These findings suggest that recognition of self-associated antigens is a potentially important cause of HIV-1 reservoir expression, which can contribute to persistent systemic inflammation and rebound upon ART interruption.