MultiOMICS to uncover immune and virological mechanisms that drive HIV DNA decay, restore immune homeostasis, and promote HIV specific immunity in PWH receiving cell therapies.

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ABSTRACT Immune cell-based therapies have been postulated to be able to induce HIV remission and facilitate antiretroviral therapy (ART) discontinuation. To date, allogeneic stem cell transplantation (allo-HSCT) with CCR5∆32/∆32 donor cells is the only medical intervention that has been able to cure HIV in up to five reported cases. Allo- HSCT also results in a dramatic reduction in the HIV reservoir even when using non-mutated CCR5 donor cells. Passive transfer of autologous CCR5-modified CD4 T cells has emerged as a more affordable, less-risky, alternative to reinstate an HIV-refractory immune cell milieu. In this proposal we will define the role of the host environment (including host/non-host metabolites) on virological and immunological outcomes. To this end we will access PBMCs and plasma, and clinical metadata from three independent study populations: the IciStem cohort (allo-HSCT) and 2 cohorts of subjects infused with autologous CCR5-modified CD4 T cells. We hypothesize that a pre-intervention plasma milieu (microbiota associated metabolites and cytokines) allows for better engraftment of both allo-HSCT and autologous CCR5-modified CD4 T cells which is associated with reduced HIV reservoir and rejuvenation of CD4 and CD8 memory stem cells (Tscm) and effector cells and innate cell antiviral responses that limit HIV rebound upon ATI. In aim1 we will identify the impact of the host environment driving the heterogeneity of virological features including frequencies of cells with intact provirus integrity of viral sequences, integration sites and translation competence prevalent during long-lasting viral control pre-intervention and which can impact on the kinetics of viral load rebound and immune reconstitution post engraftment. In aim 2 we will identify the impact of host environment on the magnitude of host-donor chimerism, innate immune activation and stem-like CD4+ T-cell associated immune reconstitution. Our preliminary data show that frequencies of HIV resistant CD4 TSCM are the best predictors of long-term control of viral load post adoptive transfer of autologous CD4 T cells. Microbial and host metabolites are important modulators of the differentiation and effector function of innate and adaptive immune cells. Hence selected pro- inflammatory metabolites could impact on the development of these T cell stem cells and as well HIV resistant myeloid cells by promoting their activation and differentiation and this will impede on BM engraftment. In aim 3 we will define parallel virological and metabolic mechanisms that are associated with viral control post autologous CCR5 modified CD4+ T-cell therapy and all-HSCT intervention. The virological features listed above, and the host and environmental features cited in Aims 1 and 2 will impact on adoptive transfer of autologous HIV resistant CD4 T cells as they did for BMT. The experimental design includes virology, immunology and multiomic cutting edge technologies which will be integrated to provide novel validated mechanistic evidence as to the role of host factors in shaping the heterogeneity of the response to immune cell-based therapies in HIV cure strategies.