Immune determinants of pediatric HIV/SIV reservoir establishment and maintenance

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ABSTRACT – Project 3 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 children living with HIV (CLWH) can be created. The knowledge gap we address in Project 3 is how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system, with specific focus on host and bacterial metabolites, immunoregulatory cytokines, and thymic output. HIV persistence in adults is driven by recognizable metabolomic and microbial profiles that include metabolites modulating epigenetic changes in genes regulating innate/adaptive immune cell function and HIV latency. Studies in CLWH clearly demonstrate that the size of the HIV reservoir is variable with a high dynamic range. The hypothesis to be tested in Project 3 is that age- associated changes in HIV reservoir size and stability are driven by specific metabolites that influence CD4+ and CD8+ T cell function, cytokine production (e.g., IL-10 and TGF-β), and the level of HIV-infected recent thymic emigrants (RTEs). In Aim 1, we will quantify the contribution of thymic output and infected RTEs to changes in the size of the intact HIV reservoir. We will test the impact of the anti-inflammatory cytokine environment prevalent in younger age groups on thymic output and HIV reservoir seeding. In Aim 2, we will address how innate and adaptive cellular immune homeostasis and HIV-specific immune function are influenced by the host environment and thymic output using high-dimensional flow cytometry, cytokine analyses and transcriptional/epigenetic profiling on single cells. In Aim 3, we will decipher the impact of microbial/host metabolites on production of IL-10 and TGF-β, establishment and maintenance of HIV reservoirs, and innate/adaptive immune functions. Targeted metabolomics to quantify short chain fatty acids and primary/secondary bile acids will be used to define and validate relationships with levels of intact and translation competent HIV DNA. Finally, immunological, virological, and molecular data will be integrated, and machine learning algorithms will be used to develop models to predict the magnitude and features of HIV reservoirs. Longitudinal samples from two cohorts of CLWH (IMPAACT biorepository and EPIC4 study) allow us to monitor dynamics of HIV reservoirs across childhood. 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 expertise with cutting-edge systems immunology to deeply interrogate HIV. With multidisciplinary approaches, synergies across Projects and Cores, and our highly collaborative group of established and early-stage investigators, we are confident that Project 3 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.