Antagonism of Host Cell Restriction and Sensing by HIV-1 Nef

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The goal of this proposal is to dissect the molecular mechanisms behind the restriction to HIV-1 virion infectivity by Serinc5 (S5) and the Nef-mediated antagonism thereof. Our results obtained during the first funding period revealed antagonism of virion-associated S5 as novel principle of Nef antagonism, defined a S5 antagonism motif (S5AM) in the N-terminus of Nef as novel determinant of Nef antagonism, and ruled out that S5 exerts its antiviral activity by altering lipid composition and organisation of HIV particles. In addition, we found that S5 sensitizes HIV-1 particles to enhanced innate immune recognition by monocyte-derived macrophages (MDMs) but not CD4 T lymphocytes. In the second funding period we will build on these results and the collaborative network of the SPP to (i) unravel how Nef antagonises the S5 restriction to HIV-1 particle infectivity with emphasis on the molecular mechanism of action of the S5AM and (ii) dissect mechanism and relevance of S5-mediated induction of innate immune recognition of HIV-1 particles by MDMs. Together, these investigations will yield a comprehensive understanding of the complex interplay between SERINC proteins and viral antagonists in retrovirus replication and pathogenesis.