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

Interventions to induce lasting human immunodeficiency virus (HIV) remission are needed to obviate the requirement for lifelong antiretroviral therapy. Durable post-intervention control (PIC) of viraemia has been achieved in a subset of people following administration of broadly neutralizing anti-HIV-1 antibodies (bNAb) and analytical interruption of treatment^1-4. Previous studies support a role for CD8⁺ T cells in PIC^5-9, but the precise features of CD8⁺ T cells involved remain unclear. Here we mapped and functionally profiled CD8⁺ T cell responses to autologous HIV epitopes using longitudinal samples from four analytical treatment interruption 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 increased further following bNAb administration without emergence of new clonotypes targeting defined HLA-optimal epitopes. Multi-modal 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.