Immune determinants of pediatric HIV/SIV reservoir establishment and maintenance

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ABSTRACT - Overall New perinatal HIV infections continue, at a rate of about one every 3-4 minutes, 400 every day, and 3000 every week. For children living with HIV (CLWH), antiretroviral therapy (ART) greatly reduces mortality and morbidity; however, viral rebound quickly ensues if ART is stopped. HIV persistence in a latent reservoir in CD4+ T cells that can give rise to rebound viremia is the major barrier to a cure. However, there remains a significant knowledge gap regarding how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system. The overall objective of this Program project application is to generate a comprehensive understanding of the complex host-pathogen interactions critical for HIV reservoir seeding and persistence such that novel cure strategies truly targeted for the unique immune environment of CLWH can be created. Our central hypothesis is that the host immune environment during the perinatal period and throughout childhood and adolescence, influenced by host/microbial metabolites and thymic output, determines the efficacy of HIV-specific immunity and the nature of reservoir establishment and maintenance. To test this hypothesis, we have compiled an outstanding team of experienced scientists and early-stage investigators (ESIs) from the Departments of Pediatrics and Pathology at Emory School of Medicine, with collaborators from the NIH, Kirby Institute, and the Université de Montréal. The research proposed builds upon the strong existing collaborations that generated the rigorous foundational research in support of each Project and develops links between new collaborators. Program oversight, communication plans, and mentoring of ESIs will be coordinated through the Administrative Core. We propose multiomic experiments in Projects 1-3 with data centralization in the Bioinformatics Core. The overall Specific Aims of our Program are: 1) To investigate the impact of IL-10, TGF-β, and thymic output on immune function and reservoir establishment and maintenance in perinatal HIV/SIV infection; 2) To determine the role of CD8+ T cells in reservoir establishment and maintenance in perinatal HIV/SIV infection; 3) To generate integrative models that define the host immune determinants of HIV/SIV reservoir establishment and maintenance and predict the size and nature of the HIV reservoir in CLWH. This deep dive into pediatric immunology will allow for insights to emerge that would not be possible if each Project were performed in isolation. A better understanding of the vulnerability of HIV reservoirs to innate and adaptive immune pressure will drive informed approaches to a cure for CLWH. The research proposed builds on our team’s expertise, the rich resources available at Emory School of Medicine, Emory National Primate Research Center, Emory Center for AIDS Research, and generous access to biospecimens from two cohorts of CLWH. We are confident that this Program will lead to important discoveries regarding immune regulation of the pediatric HIV reservoir and immune dysfunction. It is our mission to turn these discoveries into clinical trial protocols to advance research towards a cure for children with HIV.