CD8+ T cell stemness precedes post-intervention control of HIV viraemia
Zahra Kiani, Jonathan M. Urbach, Hannah Wisner, Mpho J. Olatotse, Daniel Y. Chang, Joshua A. Acklin, Alicja Piechocka‐Trocha, Nathalie Bonheur, Ashok Khatri, Mathias Lichterfeld, Jesper Damsgaard Gunst, Ole S. Søgaard, Marina Caskey, Michel C. Nussenzweig, Bruce D. Walker, David R. Collins
Abstract
Abstract 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.