PROJECT SUMMARY The primary goals of the proposed study are to determine the impact of autologous neutralizing antibodies in selecting the rebounding HIV variants after treatment interruption and contributing to HIV post-treatment control. Although the majority of HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. Our analysis of the CHAMP study of HIV PTCs has shown an increase in post-treatment control for individuals initiating ART early after infection. However, key knowledge gaps in the field include our incomplete understanding of which viral variants will lead to HIV rebound after treatment interruption (i.e., the “reboundable reservoir”) and mechanisms behind post- treatment control, including how early ART initiation lowers the barrier to HIV remission. Neutralizing antibodies represent a key adaptive immune response against a broad range of viruses. While anti-HIV antibodies arise during untreated acute infection, maturation of the immune response requires time, as it can take several months before potent autologous neutralizing antibodies (aNAbs) against HIV are developed. However, continuous viral replication in the absence of ART allows for rapid viral escape and renders the humoral response largely ineffective in controlling HIV infection. Early ART initiation has been found to restrict the size and diversity of the HIV reservoir, while preserving B-cell antiviral immunity. In this proposal, we plan to assess the role of aNAbs in selecting for rebounding viral variants and mediating post-treatment HIV control. The proposed studies have the potential to lead to key paradigm shifts in the field, including that anti-HIV immune responses can mature and evolve after early ART initiation, that the viral populations driving HIV rebound during ART interruption is not a purely stochastic process, and provide the first mechanistic explanation behind the ability of early-ART initiation to lower the barrier to HIV remission.