Establishing reliable predictors of viral rebound in HIV treatment interruption is a prerequisite to accelerating the development of effective HIV cure and eradication strategies. The definition of such predictors is, however, complicated by the diverse clinical histories of each infected individual and the variable levels of host immunity levied against the virus, As therapeutic vaccination is considered a critical component of the HIV cure agenda, immune predictors of virus control should ideally also be assessed in the context of the most advanced and potent vaccine strategies available and in individuals with maximally maintained immune function. In Project 1 of this P01 program we will take advantage of having conducted a series of clinical trials that provide an extraordinarily rich sample base from past, ongoing and future treatment interruption trials that, in some cases, are combined with the most immunogenic and promising therapeutic vaccine candidates to date. We will use this privileged situation to test the hypothesis that HLA-E restricted T cell responses impact viral reservoir activity and the kinetics of viral rebound and that additional host factors and viral reservoir characteristics enhance this effect. The hypothesis is based on intriguing data from the SIV model, where Mamu-E restricted T cell responses have been implicated in vaccine-mediated virus control, and our own extensive preliminary data linking epigenetic modification of critical host factors, including HLA-E, to viral control in untreated HIV infection. Together with data from Project 3 and validation experiments in monkey models in Project 2, we will address the question of whether strong HLA-E restricted responses discordantly affect myeloid and lymphoid reservoirs that leads to changes in reservoir and rebounding virus composition. If successful, the expected data will establish markers of successful therapeutic vaccination and effective control of viral rebound in HIV cure strategies.