PROJECT SUMMARY The HIV reservoir is a population of latently HIV infected cells that persists in people living with HIV on suppressive antiretroviral therapy (ART) and prevents cure of HIV. Dr. Reeves and colleagues will study the mechanisms that create and sustain the HIV reservoir throughout treated and untreated infection. This team will use a mathematical modeling approach to integrate existing published and unpublished as well as novel experimental data ranging across five stages of infection: early and chronic untreated (Aim 1) and early and long-term treated, and analytical treatment interruption (Aim 2). Data will consist of HIV viral loads and genetic sequences (RNA and DNA), cell counts (CD4+ and CD8+ T cells), and clonality of CD4+ T cells defined by T cell receptor sequencing. We will adopt a novel within-host phylodynamic “wiphy” model to specifically study HIV reservoir biology by specifically interrogating the various mechanisms driving its persistence vs. clearance – including cellular proliferation of infected cells and adaptive immune selection against certain HIV sequences. We will determine which mechanisms predominate in which stages, and provide a comprehensive understanding of HIV reservoir creation, maintenance, and evolution throughout all infection stages. This research will aid in the building of next-generation models of HIV reservoir seeding and persistence dynamics. This work will help the HIV cure field gain a deeper understanding of how the HIV reservoir is created during untreated infection and maintained during treated infection. Results should aid in efforts to design therapeutics towards a functional or sterilizing HIV cure.