HIV-1利用CypA躲避TRIM11加速脱衣壳作用的机制研究

Early post entry into host cells, HIV-1 begins disassembly of the protective core consisting of capsid, in a process called uncoating. This process is highly regulated that perturbation of uncoating impedes reverse transcription and severely inhibits HIV-1 replication. Thus, the study of the interaction between HIV-1 and host proteins during uncoating process is of great help for developing new antiviral therapies. Our previous studies revealed that human TRIM11 reduces HIV-1 reverse transcription by accelerating the uncoating process once it recognizes viral capsid, which is antagonized by capsid-interacting protein CpyA. Thus, we propose that HIV-1 may exploit CypA as a cover to escape recognizing by TRIM11. In this study we will examine the binding capacity of TRIM11 with HIV-1 capsid and the accelerating effect of TRIM11 on viral uncoating when the interaction between CypA and HIV-1 capsid is disrupted using a combination of inhibitor treatment and genetic approaches to assess the effect of CypA on TRIM11-mediated premature disassembly of viral capsid core. Furthermore, we will investigate if the interaction between CypA and the Capsid core from viruses that evolve under the pressure of TRIM11 overexpression will change. We hope our research would elucidate the mechanisms by which HIV-1 escapes from antiviral function of TRIM11 and provide theoretical basis for understanding the relationship between host and HIV-1 during viral uncoating.

HIV-1进入宿主细胞后的脱衣壳过程受到了严格的调控。该过程的紊乱将降低病毒的逆转录水平，从而抑制其复制。因此研究病毒在脱衣壳过程中与宿主蛋白的相互作用对研发新的抗病毒方案具有重要意义。前期研究发现TRIM11（T11）能通过加速HIV-1脱衣壳抑制病毒的复制，而这一作用受到衣壳结合蛋白CypA的拮抗。因此推测HIV-1可能利用CypA躲避T11的加速脱衣壳作用。本项目拟通过药物处理及遗传学手段在CypA不能与病毒衣壳结合状态下，检测T11与衣壳的结合及对病毒加速脱衣壳的能力，明确CypA在T11诱导病毒脱衣壳中的作用；通过病毒进化实验，检测HIV-1在T11过表达压力下产生的突变是否改变了衣壳与CypA的结合能力，进一步明确这两种蛋白在病毒脱衣壳过程中的作用关系，以期阐明HIV-1逃逸T11作用的分子机制，为深入理解HIV-1在脱衣壳过程中与宿主之间的拮抗关系提供理论基础。