Targeting the HIV-1 pathogenesis factor Nef
The Nef protein of HIV-1 is key for pathogenesis and disease progression by serving as versatile protein interaction adaptor that rewires many host cell properties and pathways to the benefit of the virus. Owing to its multiple functions and relevant protein-interaction motifs, Nef is not yet targeted therapeutically. We recently identified a protein interaction surface that mediates all cardinal Nef functions (Ananth et al., 2019, J. Virol.; Kaw et al., 2020, Embo J). The goal of the project is to develop a microscopy-based screening platform to identify lead compounds of a broadly acting Nef inhibitor and to dissect the mechanism of action of this protein interaction surface. This will involve the development of an advanced microscopy acquisition and analysis pipeline and applying immunology, biochemistry and cell biology approaches. For this project, we are looking for candidates with strong background in microscopy and cell biology.
Dissecting innate immune restrictions to HIV-1 in resting CD4 T cells
While HIV-1 efficiently replicates in activated CD4 T cells, many barriers at different steps of the viral life cycle prevent productive infection of resting CD4 T cells (Pan et al., 2013, Cell Research). A recently developed gene editing method allows us for the first time to address the molecular bases of these restrictions without altering the activation state of these cells (Albanese et al., 2022, Nat. Methods). Exploiting this novel technology, the project aims at dissecting identity and mechanism of these restrictions and at assessing how they are alleviated by T cell activation. These analyses will involve advanced virology, microscopy and cell biology approaches in primary human cells and include work with replication competent HIV-1 (BSL3 laboratory). Prior experience with the purification and manipulation of primary human CD4 T cells and with experimental HIV-1 infection will be required for this project.