CD8+ T cell recall cytotoxicity during chronic treated HIV-1 infection is associated with limited reservoir size and activity

HIV-1 persists during antiretroviral therapy (ART), resulting in rebound viremia after treatment interruption. HIV-specific CD8+ T cell functionality is typically not restored by ART but may improve following prolonged treatment and was recently associated with post-intervention viral control. To evaluate the prevalence and impact of T cell immune function on HIV-1 persistence during prolonged ART, we mapped and functionally characterized CD8+ T cell responses that target virus reservoirs in sixty people with HIV-1 (PWH) who initiated therapy during chronic infection. Unexpectedly, 17% of participants exhibited robust proliferation and recall cytotoxicity against one or more autologous proviral epitopes at levels commensurate with spontaneous HIV-1 controllers, a group representing less than 1% of PWH. These functional responses were associated with smaller and less transcriptionally active HIV-1 reservoirs during ART. During an analytical treatment interruption, in vivo cytotoxic recall of phenotypically divergent HIV epitope-specific CD8+ T cell clonotypes trailed viral rebound but coincided with its attenuation prior to ART resumption. Our study reveals the unexpected prevalence of highly functional CD8+ T cells targeting autologous HIV-1 reservoirs among treated PWH and their potential impacts on viral persistence and rebound. These findings underscore a need for multimodal immunotherapeutic strategies capable of eliciting, restoring, or accelerating recall cytotoxicity toward achieving durable and scalable HIV-1 remission.