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

The combination of replication-competent HIV-1 proviral persistence and virus-specific immune dysfunction prevents virus clearance during antiretroviral therapy (ART), resulting in rebound viremia after treatment interruption. Functional impairment of HIV-specific CD8+ T cells during chronic infection is typically not reversed by ART but has recently been shown to improve in some individuals after prolonged treatment. To evaluate the impact of cellular immune function on viral persistence, we mapped and functionally characterized HIV-1 epitope-specific CD8+ T cell responses and virus reservoirs in sixty people with HIV-1 (PWH) who initiated prolonged ART during chronic progressive infection. In 17% of participants, recall cytotoxicity of proliferative CD8+ T cells targeting one or more autologous proviral epitopes was comparable to responses in spontaneous HIV-1 controllers. These responses were associated with smaller and less transcriptionally active HIV-1 reservoirs during prolonged ART. Treatment interruption in one participant with moderately high HIV-specific CD8+ T cell proliferative and cytolytic capacity resulted in a rapid reduction of rebound viremia coincident with in vivo HIV-specific CD8+ T cell expansion and secondary cytotoxic effector cell differentiation. Collectively, these results highlight a potential role for recall cytotoxicity in limiting HIV-1 persistence during ART and attenuating rebound viremia after treatment interruption, which may inform strategies to elicit durable post-ART immune control.