Characterization of HIV infection in resting CD4 T-cells

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Resting CD4 T-cells are resistant to productive HIV infection, yet are massively depleted during disease progression and represent a major reservoir for the virus in HIV-infected individuals. The goal of the second funding period of this collaborative and interdisciplinary research proposal is to unveil and characterize barriers to and regulators of HIV replication and cell death in resting CD4 T-cells. Building on exciting results from the first funding period and newly established protocols for efficient gene knockouts (KO) and optimized cultivation conditions in resting CD4 T-cells, we now aim in four work packages to (i) perform a fundamental characterization of host dependency factors for HIV-1 infection in this primary cell type, (ii) genetically evaluate the potency of novel cellular Vpx interactors - identified by proteomic approaches - for the early post-entry phase of HIV, (iii) characterize the profile and functional relevance of putative cellular factors involved in restriction and sensing of HIV, and (iv) adapt the KO approach to the tonsil histoculture ex vivo model to dismantle sensing machineries and signaling pathways that critically contribute to immunodepletion during HIV-1 infection in complex lymphoid tissues. Collectively, these studies will increase our molecular and pathophysiological understanding of the multi-faceted interactions of HIV-1 with resting CD4 T-cells.