Autologous neutralizing antibodies and polyfunctional T cells contribute to long-term HIV-1 post-intervention control

Antiretroviral therapy (ART) interruption typically leads to rapid HIV-1 viral rebound in people with HIV-1. To develop an HIV-1 cure, insight into immunological mechanisms capable of preventing HIV-1 viral rebound is urgently needed. Here, we describe three exceptional post-intervention controllers (PICs) who maintained ART-free virological control for >6.5 years (ongoing), >7.5 years (ongoing) and 2.5 years following administration of broadly neutralizing antibodies. PICs had quantifiable genetically intact/inducible infectious proviral reservoirs that were increasingly clonal and located in nongenic/centromeric chromosomal regions, indicating immune-mediated selection. Potent autologous neutralizing antibodies and polyfunctional HIV-1-specific CD4⁺ and CD8⁺ T cell responses, pre-programmed for antigen response, were present before, and persisted during, ART interruption. In one PIC, viral rebound following 2.5 years of ART-free control was associated with accumulated viral mutations that resulted in escape from neutralizing antibody and T cell responses. Collectively, our findings support developing HIV-1 curative strategies aimed at enhancing pre-existing adaptive immune responses.