A cytoplasmic tail determinant in HIV-1 Vpu mediates targeting of tetherin for endosomal degradation and counteracts interferon-induced restriction.

摘要: The HIV-1 accessory protein Vpu counteracts tetherin (BST-2/CD317) by preventing its incorporation into virions, reducing surface expression, and ultimately promoting degradation. Here we characterize a putative trafficking motif, EXXXLV, in the second alpha helix of subtype-B cytoplasmic tail as being required for efficient antagonism. Mutation this motif prevents ESCRT-dependent degradation tetherin/Vpu complexes, cell downregulation, but not physical interaction with Vpu. Importantly, is cell-free virion release from CD4+ T cells, particularly after their exposure to type-1 interferon, indicating that ability reduce levels promote important counteract restriction under conditions virus likely encounters vivo. EXXXLV mutants accumulate at endosomal compartments, retain bind both β-TrCP2 HRS, post-binding event commits transit plasma membrane viral budding zones. We further found while function dependent on clathrin, entire can be functionally complemented clathrin adaptor binding peptide derived Nef, none canonical adaptors nor retromer are process. Finally show residual activity requires an intact endocytic tetherin, suggesting association during recycling may sufficient compromise some degree.