中科院学者973项目发表JBC文章解析HIV-1复制

　　

　2016年1月6日，国际学术期刊Journal of Biological Chemistry 在线发表了中国科学院上海巴斯德研究所王建华课题组的最新研究成果，揭示宿主因子调控HIV-1复制新机制。

　　HIV-1属于逆转录病毒，其感染细胞、完成复制周期主要包括以下几个环节：病毒通过受体和辅助受体结合宿主靶细胞（主要是CD4+ T细胞）、脱壳、逆转录合成双链cDNA进入细胞核然后整合到宿主基因组上、病毒基因的转录和剪切、病毒mRNA至细胞质的转运、病毒蛋白的翻译和病毒颗粒的包装、出芽和成熟等。HIV-1复制周期的每一个环节都高度依赖于宿主蛋白的表达。鉴定调控HIV-1复制的关键宿主蛋白有利于寻找抗病毒靶标。

　　课题组曾利用基因组学筛选了多种潜在调控HIV-1复制的宿主蛋白，其中Naf1(HIV-1 Nef-associated factor 1) 是可在细胞核/质间穿梭的宿主因子。博士研究生任晓新等在研究员王建华的指导下，发现Naf1可促进HIV-1未剪切gag mRNA的出核；Naf1这一功能依赖于与另外一个宿主因子CRM1（Chromosome region maintenance 1）的相互作用，并且与Naf1在细胞核/质间穿梭特性相关。研究结果揭示宿主因子Naf1调控HIV-1复制机制，为抗病毒药物设计和基因治疗提供了潜在的宿主靶点。

　　该研究得到来自中科院、国家基金委、科技部艾滋病和病毒性肝炎重大传染病防治专项及“973”等项目的资助。

 

　　图：Naf1与CRM1相互作用促进HIV-1复制。（A）激光共聚焦显微镜观察Naf1在细胞核和细胞质的分布；（B）示意图：Naf1与CRM1相互作用促进HIV-1未剪切HIV-1 gag mRNA的出核。

原文摘要：

HIV-1 Nef-associated factor 1 enhances viral production by interacting with CRM1 to promote nuclear export of unspliced HIV-1 gag mRNA

HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-κB activation through binding to A20, and the loss of Naf1 controlled NF-κB activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection.