SERINC5 exerts a post-integration block to HIV-1 gene expression in macrophages
HIV-1 antagonizes SERINC5 via redundant mechanisms, primarily via Nef and additionally via envelope glycoproteins. Paradoxically, the HIV-1 isolates that confer resistance to SERINC5 via envelope also preserve Nef function in ensuring its exclusion from virion incorporation, suggesting additional, cell-nonautonomous roles of this host factor. Here we uncover an unusual mode of SERINC5 action in inhibiting viral gene expression by reducing viral mRNA capping. This inhibitory effect is observed only in the cells of the myeloid lineage, but not in epithelial or lymphoid origin. Further, we find that the host genes, RPL35 and DRAP1 are induced upon the challenge of macrophages with SERINC5-laden viruses and that a mammalian capping enzyme, MCE1, as a common interactor of RPL35 and DRAP1. HIV-1 Tat interacts with MCE1 and recruits it for efficient HIV-1 RNA capping. We demonstrate that SERINC5 induces the MCE1 interaction with RPL35 and DRAP1 while abrogating its association with Tat. This results in reduced viral RNA capping by two orders of magnitude and consequently affects HIV-1 gene expression. The regulation of a post-integration event by SERINC5 exemplifies its novel antiviral function in myeloid cells thus overcoming virus-acquired resistance via envelope divergence.