Immune determinants of pediatric HIV/SIV reservoir establishment and maintenance

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ABSTRACT – Project 2 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 2 is how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system, with specific focus on the cytolytic and non-cytolytic antiviral role of CD8+ T cells. The drivers of reservoir persistence in CLWH are incompletely understood and the complexity of the pediatric innate and adaptive immune system across developmental stages contributes to the challenge of a finding cure for HIV. Mounting evidence in adult models implicates CD8+ T cells as being required for maintaining HIV suppression under antiretroviral therapy (ART) and we have recently found that the viral reservoir seeded after infection does not depend on the classical cytolytic function of antigen-specific CD8+ T cells. The hypothesis to be tested in Project 2 is that the CD8+ T cell-mediated HIV/SIV pro-latency effect will be reproducible in pediatric models; however, distinct features of this non-classical role for CD8+ T cells may be influenced by the regulatory immune environment in early life. In Aim 1, we will develop pediatric in vitro models to thoroughly investigate the mechanisms involved in CD8+ T cell-mediated control of HIV/SIV latency in infants and children via comparative immunophenotyping, transcriptomic, and virological analyses in presence or absence of CD8+ T cells. In Aim 2, we will conduct a proof-of-principle in vivo study using experimental antibody mediated CD8+ cell depletion in rhesus macaque (RM) infants prior to infection with SIVmac239M. To assess the role of CD8+ T cells in SIV reservoir establishment we will compare viral dynamics and viral reservoir size/diversity/integration sites on ART and virus rebound after ART interruption between CD8-depleted and undepleted RM infants. In Aim 3, antibody-mediated CD8+ cell depletion will be performed in SIVmac239M-infected RM infants after long-term ART with and without an LRA to test the extent to which removal of CD8+ T cells disrupts reservoir maintenance. CD8+ T cell-mediated mechanisms involved in latency reversal will be further assessed through multiomic analyses. 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 infant RM models, state-of-the-art reservoir assays, and T cell immunology to deeply interrogate pediatric HIV/SIV. With multidisciplinary approaches, synergies across Projects and Cores, and our highly collaborative group of established and early-stage investigators, we are confident that Project 2 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.