Expansion of stemlike HIV-specific CD8+ T cells and limited viral epitope diversity characterize durable posttreatment control of HIV.

Individuals who durably control HIV after cessation of antiretroviral therapy (ART) are of great interest for HIV cure efforts, but the correlates of posttreatment control remain incompletely understood. Here, we show across a diverse cohort of posttreatment controllers (PTCs), posttreatment noncontrollers (NCs), and spontaneous elite controllers (ECs) that robust expansion of HIV-specific CD8+ T cells and reduced viral reservoir diversity were strongly associated with durable (>1 year) viral suppression after ART cessation. In addition, HIV-specific CD8+ T cells in PTCs exhibited a stemlike memory phenotype, characterized by high TCF-1 (T cell factor 1) and low TOX (thymocyte selection-associated HMG box) expression, and readily differentiated into cytolytic effectors. Mapping of CD8+ T cell responses from PTCs revealed broad targeting of epitopes in a conserved autologous reservoir, whereas preferential targeting of epitopes derived from mutationally constrained regions was primarily a feature of CD8+ T cells from ECs. Univariable and additive analyses revealed a link between HIV-specific CD8+ T cell expansion, a stemlike phenotype, and conservation of human leukocyte antigen class I-restricted viral epitopes with posttreatment control. Together, these findings identify features of HIV-specific CD8+ T cells and the viral reservoir that are associated with sustained HIV control after ART cessation, informing future immunotherapeutic strategies toward achieving an HIV cure.