Pediatric Adolescent Virus Elimination (PAVE) Martin Delaney Collaboratory

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ABSTRACT The immediate establishment of the latent HIV-1 reservoir in resting memory CD4+ T cells precludes HIV-1 cure, compelling ART for a lifetime in children. The mission of the PAVE Collaboratory is to use cutting-edge science to establish a deep and broad understanding of the immunopathogenesis of pediatric HIV-1 reservoirs, across the age spectrum, and to demonstrate preclinical safety and efficacy of novel therapeutics to eradicate reservoirs and control rebound that will pave the way for future interventional human studies toward a lifetime of sustained HIV-1 control off ART. We hypothesize that the unique features of the infant immune system at the time of reservoir establishment impact the characteristics of long-term virus persistence, susceptibility to immune- mediated clearance, and reactivation that are distinct from adult infections, warranting in-depth investigation to inform cure therapeutics suitable for children. We will test this hypothesis and execute the PAVE Scientific Agenda through accomplishment of the following Specific Aims: 1. Define the establishment and evolution of the HIV latent reservoir in perinatal infection. 2. Enhance pediatric immunity and broadly neutralizing antibody (bNAb) delivery to achieve post-treatment control of HIV-1 off ART. 3. Deploy immune-targeted strategies to eliminate virus reservoirs. 4. Optimize virologic, immunologic, and imaging methods to assess efficacy of HIV-1/S(H)IV cure interventions. 5. Foster community engagement in pediatric HIV cure research. The PAVE program is multidisciplinary, multicultural, and iterative with a nimble structure encompassed by four highly synergistic Research Foci and a domestic and international community program that will rapidly incorporate new scientific directions and feedback from our stakeholders. The PAVE leadership team spans diverse scientific expertise and exhibits additional diversity in terms of gender, academic rank, and country of origin. Each of the Research Foci also includes junior faculty co-Investigators to facilitate their career development within the HIV-1 research space. Through the collective efforts of our scientific leadership, Executive Committee, Scientific Advisory Board, investigators, industry partners, network collaborations, and domestic and international community program, PAVE anticipates meeting the following overall milestones of: 1) understanding early life immunity and early antiretroviral treatment on the composition and stability of the latent reservoir, including in naïve T cells, and potential for HIV-1 remission; 2) eliminating of these reservoirs in pre-clinical studies of immune-targeted strategies; 3) defining the role of myeloid cells in HIV-1 persistence and rebound, including in the CNS; 4) establishing novel approaches to enhance pediatric immunity through active and passive immunization; 5) developing cutting-edge approaches to quantify and monitor proviral reservoirs to measure clinical trial efficacy, and 6) promoting active community engagement in pediatric HIV-1 cure research. These milestones will help achieve the vision of sustained ART-free control of HIV-1 replication in pediatric populations.