GTPase家族蛋白A调控HIV-1永久潜伏的分子机制研究

目前，实现艾滋病功能性治愈最主要的障碍是“潜伏库”的存在。针对“潜伏库”的治疗策略有“Shock and Kill” 和“Block and Lock”，当前聚焦于前者的研究较多，但存在现有的激活方式不足以完全激活潜伏的病毒，以及激活后的病毒发生再次潜伏的问题。我们从“Block and Lock”策略设计，搜集了HIV-1感染后长期不进展者样本，前期通过蛋白质质谱分析获得差异蛋白表达谱；并对目标蛋白进一步筛选，确定了其中GTPase家族的一个重要成员蛋白A，具有强的广谱的抗HIV-1不同亚型病毒及其在潜伏中的重要作用。本项目拟深入揭示蛋白A使HIV-1感染者长期潜伏，不发病的分子作用机制。本项目的实施，可实现针对“Block and Lock”设计的抗艾滋病药物，并为保持HIV-1感染者一直处于潜伏状态、实现功能性治愈的理论支持。

Nowadays, the major obstacle to achieve the goal of functional cure of AIDS is the existence of "latent reservoir". Treatment strategies for "latent reservoir" include "Shock and Kill" and "Block and Lock". At present, there are many studies focusing on the former strategy, but the present activation methods are not efficient enough to fully activate the latent virus, and the re-latency of the activated virus may occur. From the design of the "Block and Lock" strategy, we collected samples of long-term non-progressors and normal progressors and performed the protein mass spectrometry analysis, different protein expression profiles of two types of HIV-1 infected patients were obtained. We then screened the candidate proteins and identified an important member of the GTPase family-protein A as the target protein. Protein A has strong and broad-spectrum ability to inhibit different subtypes of HIV-1 and critical role in maintaining the latency of HIV-1. This project aims to further explore the underlying molecular mechanism of protein A in maintaining the long-term latency of HIV and remaining the patients disease-free. The implementation of this project will accelerate the anti-AIDS drugs designed for "Block and Lock", and provide the theoretical basis for keeping HIV-1 infected people in a latent state and achieving the functional cure of AIDS.