CD8+ T cell stemness precedes post-intervention control of HIV viremia

Interventions to induce lasting HIV remission are needed to obviate the requirement for lifelong antiretroviral therapy (ART). Durable post-intervention control (PIC) of viremia has been achieved in a subset of individuals following broadly neutralizing anti-HIV-1 antibody (bNAb) administration and analytical treatment interruption (ATI)1-4. Prior studies support a role for CD8+ T cells5-9 but the precise features of CD8+ T cells involved in PIC remain unclear. Here we mapped and functionally profiled CD8+ T cell responses to autologous HIV epitopes using longitudinal samples from four ATI trials in bNAb recipients. PIC was associated with superior pre-intervention HIV-specific CD8+ T cell proliferative capacity, stem cell-like memory phenotype, and recall cytotoxicity against autologous HIV peptide-pulsed CD4+ T cells. CD8+ T cell stemness was further increased following bNAb administration without emergence of new clonotypes targeting defined HLA-optimal epitopes. Multimodal single-cell analyses revealed molecular features associated with PIC and HIV-specific CD8+ T cell stemness, including signatures of metabolic fitness and reduced T cell exhaustion. These results identify immune features that precede subsequent PIC to inform the development of combination immunotherapies that will elicit durable HIV remission.