Identification of constitutive NK cell features associated with post-treatment control of SIV infection. The pVISCONTI study

Post-treatment HIV controllers (PTC) offer a unique opportunity to uncover the determinants of durable remission after antiretroviral therapy (ART) interruption. Early ART initiation has been shown to favor this outcome, but the underlying immune mechanisms remain unclear. Recent reports suggest that natural killer (NK) cells may play a key role in post-treatment control of infection; however, a direct association with specific NK cell features has not been firmly established. We used a recently reported model of post-treatment control of SIVmac251 infection in Cynomolgus macaques (the pVISCONTI study) to analyze the constitutive and infection-induced characteristics of NK cells and their association with post-treatment viral control. Studying six PTC and six post-treatment non-controllers, we identified two NK cell subsets differing in the expression of NKG2A, NKp30, and NKp46, and which abundance prior to infection showed opposite associations with the outcome after ART interruption. NKG2Ahigh NK cells lacking NKp30/NKp46 (NKG2AhighNKp30-NKp46-), shaped by the MHC background of the animals, were linked to improved post-treatment control. This subset displayed tissue-homing potential and preserved functionality despite infection, characterized by cytokine production and degranulation. Conversely, NKG2AlowNKp30+NKp46+ NK cells exhibited reduced cytotoxicity 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 indicates that constitutive NK cell features, preserved by early ART initiation, may provide a favorable immune environment for post-treatment control. These findings further identify the NKG2A axis as a potential target to improve outcomes after ART interruption.