Increasing efforts are being made to understand whether early intervention after HIV-1 infection can enable long- term viral control and reduction of the viral reservoir through the preservation of HIV-1-specific immune responses. Recently, the pioneering eCLEAR phase 1b/2a clinical trial led by MPI SØgaard, found that administration of the HIV-Env specific broadly neutralizing antibody (bNAb) 3BNC117 at antiviral therapy (ART) initiation enhanced CD8+ T cell viral immunity and enabled viral control amongst participants harboring 3BNC117-sensitive viruses. However, the mechanisms underlying this outcome remain largely unknown. Understanding The goal of this collaborative R01 (M Betts, UPenn, B Jones, Weill-Cornell University, and O. SØgaard, Aarhus University) is to define the mechanisms underlying this protective outcome in order to inform future development of targeted immunotherapy at ART initiation as an HIV cure strategy. We hypothesize that the partial success of eCLEAR can be defined in terms of both specific mechanisms of efficacious CD8+ T-cell responses and of the features selected in remaining reservoir-harboring cells. We will address this hypothesis in three integrated Aims using samples directly from the eCLEAR study. In Aim 1, we will define phenotypic, functional, and transcriptomic features of the adaptive T cell immune responses that are modulated by bNAb treatment at ART initiation (SØgaard). In Aim 2, we will define how the HIV reservoir is differentially modulated after prolonged ART treatment and within post-therapy viral controllers vs. non- controllers who received 3BNC117 (Betts). In Aim 3, we will define the ability of CD8+ T cells from eCLEAR participants who did or did not exhibit post-ART control to mediate viral control in vivo using a novel humanized mouse model. In addition, we will modulate CD8+ T cell functions within this system to uncover specific control mechanisms. The anticipated outcomes of our project are i) A comprehensive characterization of the immunologic and reservoir features associated with the partial efficacy of eCLEAR, ii) Validation of underlying mechanisms, to guide future iterations of clinical interventions at the time of ART initiation.