PDF(Pubmed)
Abstract：
Human immunodeficiency virus type 1 (HIV-1) capsid, which is the target of the antiviral lenacapavir, protects the viral genome and binds multiple host proteins to influence intracellular trafficking, nuclear import, and integration. Previously, we showed that capsid binding to cleavage and polyadenylation specificity factor 6 (CPSF6) in the cytoplasm is competitively inhibited by cyclophilin A (CypA) binding and regulates capsid trafficking, nuclear import, and infection. Here we determined that a capsid mutant with increased CypA binding affinity had significantly reduced nuclear entry and mislocalized integration. However, disruption of CypA binding to the mutant capsid restored nuclear entry, integration, and infection in a CPSF6-dependent manner. Furthermore, relocalization of CypA expression from the cell cytoplasm to the nucleus failed to restore mutant HIV-1 infection. Our results clarify that sequential binding of CypA and CPSF6 to HIV-1 capsid is required for optimal nuclear entry and integration targeting, informing antiretroviral therapies that contain lenacapavir.
摘要：
人类免疫缺陷病毒1型（HIV-1）衣壳，这是抗病毒药物来那卡巴韦的目标，保护病毒基因组并结合多种宿主蛋白以影响细胞内运输，核进口,和融合。以前,我们表明，衣壳与细胞质中的裂解和聚腺苷酸化特异性因子6（CPSF6）的结合受到亲环蛋白A（CypA）结合的竞争性抑制，并调节衣壳运输，核进口,和感染。在这里,我们确定具有增加的CypA结合亲和力的衣壳突变体具有显著减少的核进入和错位整合。然而,CypA与突变衣壳结合的破坏恢复了核进入，一体化,和感染以CPSF6依赖的方式。此外，CypA表达从细胞质到细胞核的重新定位未能恢复突变的HIV-1感染。我们的结果阐明，CypA和CPSF6与HIV-1衣壳的顺序结合是最佳核进入和整合靶向所必需的，告知含有来纳卡巴韦的抗逆转录病毒疗法。
