Constitutive natural killer cell features associated with post-treatment control of SIV infection in the pVISCONTI study.

Post-treatment HIV controllers (PTC) offer a unique opportunity to uncover the determinants of durable remission after antiretroviral therapy (ART) interruption. Here, using six PTC and six post-treatment non-controllers from the pVISCONTI study in cynomolgus macaques, we identify associations between Natural Killer (NK) cell subsets and outcomes following ART interruption. NKG2Ahigh NK cells lacking NKp30/NKp46 (NKG2AhighNKp30-NKp46-), shaped by the MHC backgrounds of the animals, were linked to improved post-treatment control; this NK subset displayed tissue-homing potential and preserved functionality despite infection, characterized by cytokine production and degranulation. Conversely, NKG2AlowNKp30 + NKp46+ NK cells exhibited reduced cytotoxic potential and elevated IL-10/IL-17A production, and their pre-infection levels were associated with higher viremia and larger viral reservoirs after ART interruption. Our study suggests that constitutive NK cell features, preserved by early ART initiation, may provide a favorable immune environment for post-treatment control. Our findings identify the NKG2A axis as a potential target to improve outcomes after ART interruption.