Clonal succession after prolonged antiretroviral therapy rejuvenates CD8⁺ T cell responses against HIV-1

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8⁺ T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8⁺ T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8⁺ T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8⁺ T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.