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.

人类免疫缺陷病毒1型（HIV-1）通过多种冗余机制拮抗丝氨酸整合因子5（SERINC5）：主要依赖负因子（Nef），其次依赖包膜糖蛋白（envelope glycoproteins）。矛盾的是，那些通过包膜获得对SERINC5抗性的HIV-1分离株，同时保留了Nef的功能以确保SERINC5被排除在病毒颗粒掺入之外，这提示该宿主因子存在额外的细胞非自主性作用。本研究揭示了SERINC5通过减少病毒mRNA加帽来抑制病毒基因表达的非常规作用模式。该抑制效应仅在髓系细胞中观测到，而上皮或淋巴来源细胞中并无此现象。进一步研究发现，用携带SERINC5的病毒侵染巨噬细胞后，宿主基因核糖体蛋白L35（RPL35）与DR1相关蛋白1（DRAP1）会被诱导表达；同时发现哺乳动物加帽酶1（MCE1）是RPL35与DRAP1的共同互作蛋白。HIV-1反式激活因子（Tat）可与MCE1结合并招募其以高效完成HIV-1 RNA加帽。我们证实SERINC5可诱导MCE1与RPL35、DRAP1的相互作用，同时阻断其与Tat的结合。这一过程使病毒RNA加帽效率降低两个数量级，进而影响HIV-1的基因表达。SERINC5对整合后事件的调控，展现了其在髓系细胞中全新的抗病毒功能，从而克服了病毒通过包膜变异获得的抗性。