High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir

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SUMMARY Strategies for achieving sustained HIV remission must target the long-lived reservoir of HIV-infected cells. These reservoirs remain a challenge to study because they make up a very small fraction of immune cells, can be located in difficult to sample anatomic sites (e.g., the central nervous system [CNS]), and are generally less well studied in individuals who undergo treatment interruption. Here we aim at answering three critical questions: (A) what are the drivers of clonal expansion, activation of HIV-1-infected cells, and viral rebound timing – is it viral factors (such as HIV-1 integration site) that provide survival benefit of the infected cells, or is it host factors (such as immune responses to antigen or HIV stimulation) that drive the proliferation of HIV-1- infected cells and viral rebound after treatment interruption (Project 1)? (B) How do HIV-1-infected cells persist and distribute between peripheral blood and the anatomical sanctuary of the CNS (Project 2)? (C) Do HIV-1 eradication strategies, such as broadly neutralizing antibodies (bnAbs), reprogram host immune effector responses, transcriptionally, epigenetically, and functionally (Project 3)? Overall, we aim at understanding the expansion dynamics, tissue distribution, and rebound predictors of HIV-1 persistence using several unique clinical cohorts and innovative methods to provide critical insight to mechanisms of HIV-1 persistence and strategies for HIV-1 eradication. We will use these samples to define the mechanisms that govern spontaneous HIV-1 reactivation during treatment interruption and the persistence of viremia despite effective antiretroviral therapy (ART), specifically exploring virus and immune mechanisms that may impact viral maintenance and rebound (Project 1). We focus on the establishment, persistence, clonal proliferation, and rebound competence in different stages of infection of HIV-1 brain reservoirs, a critically important virus sanctuary that has been a challenge to study in detail (Project 2). Lastly, we explore the immune mechanisms that impact virus reservoir dynamics and the role of host epigenetics and immune cell function in the control and pruning of the HIV-1 proviral landscape in the context of a first-in-human broadly neutralizing antibody (Project 3). These Projects will be supported by an Administrative Core and a Data Analytics & Modeling Core. 1