CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication

The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters HIV-1 infectivity and escape from host restriction factors. However, apart from the Cyclophilin A-binding loop, CA has no known interfaces with which to interact with cellular cofactors. Here we describe a novel protein-protein interface in the N-terminal domain of HIV-1 CA, determined by X-ray crystallography, which mediates both viral restriction and host cofactor dependence. The interface is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. Mutation of the interface prevents binding to and restriction by CPSF6-358, a truncated cytosolic form of the RNA processing factor, cleavage and polyadenylation specific factor 6 (CPSF6). Furthermore, mutations that prevent CPSF6 binding also relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. These results suggest that the HIV-1 capsid mediates direct host cofactor interactions to facilitate viral infection.

人类免疫缺陷病毒1型（HIV-1）基因组经由衣壳（CA）蛋白构成的外壳进入宿主细胞。CA序列的变异会改变HIV-1的感染性，使其逃逸宿主限制性因子的识别。然而，除亲环蛋白A结合环之外，目前尚未发现CA可与细胞辅助因子相互作用的已知界面。本研究报道了一个全新的HIV-1 CA N端结构域中的蛋白质-蛋白质相互作用界面，该界面经X射线晶体学解析，可同时介导病毒限制性效应与宿主辅助因子依赖性。该界面在慢病毒属中高度保守，且在六聚体晶格构象中具有可及性。对该界面进行突变，可阻断病毒与CPSF6-358的结合，同时使其免受CPSF6-358的限制性作用；CPSF6-358是RNA加工因子切割和多聚腺苷酸化特异性因子6（CPSF6）的截短胞质形式。此外，可阻断CPSF6结合的突变同样可解除病毒对核输入辅因子转运蛋白3（TNPO3）与Ran结合蛋白2（RanBP2）的依赖。上述结果表明，HIV-1衣壳可通过直接与宿主辅助因子相互作用，以促进病毒感染进程。