长链非编码RNA PSMD5-AS1在HIV-1潜伏感染中的作用及机制研究

Latent reservoirs of HIV-1 are the major obstacle to complete eradication of virus. It is urgent and necessary to explore the underlying mechanism of HIV-1 latency. Accumulating evidence has demonstrated that lncRNA play critical role in various biological process and has become the research hotspot. With the method of lncRNA microarray screen, we recently identified an lncRNA: PSMD5-AS1, which was capable of regulating HIV-1 latency. This project will focus on lncRNA PSMD5-AS1 and explore its function in HIV-1 latency. Preliminary results suggested that PSMD5-AS1 could maintain HIV-1 latency, and knockdown of PSMD5-AS1 induced reactivation of latent HIV-1. The aim of this project is to further explore the underlying mechanism of PSMD5-AS1 to regulate HIV-1 latency. We will first examine the regulation of PSMD5-AS1 on HIV-1 LTR activity; then, we will identify the target protein of PSMD5-AS1 and their signaling pathway; finally, we will analyze the association between PSMD5-AS1 expression and HIV-1 viral load and number of CD4+T cells of HIV-1 infected individuals, as well as confirm the role of PSMD5-AS1 in regulating HIV-1 latency ex vivo. This project will provide new clues to elucidate the mechanism of HIV-1 latency and lay a theoretical foundation for the development of targeted therapeutic drugs to achieve functional cure of HIV-1 infection.

HIV-1潜伏病毒库是目前彻底治愈艾滋病的主要障碍，深入揭示其产生和作用机制是当务之急。研究表明lncRNA这类数量巨大、功能复杂的分子在病毒-宿主相互作用中发挥重要作用，是当今研究热点。本项目拟聚焦于近期筛选到的能调控HIV-1潜伏感染的一种全新lncRNA：PSMD5-AS1在潜伏中的作用。前期研究结果证实PSMD5-AS1是维持HIV-1潜伏的必要条件，下调它能激活潜伏的HIV-1。接下来，本项目将对其作用机制展开深入研究：首先明确PSMD5-AS1对HIV-1转录活性的调控作用；进而找到PSMD5-AS1的靶蛋白及相关途径；最终，分析其表达水平与在HIV-1感染者病毒载量、CD4+T细胞数等的相关性，并进一步在ex vivo水平验证PSMD5-AS1对HIV潜伏的调控作用。本项目的顺利实施有望为阐明HIV-1潜伏机制提供新线索，并为靶向治疗药物的开发、实现功能性治愈提供理论支持。

HIV-1的潜伏病毒库是彻底治愈艾滋病的主要障碍，lncRNA这一类分子已经被越来越多的证据表明具有重要的生物学功能，从lncRNA入手探寻其在调控HIV潜伏中的作用将为解析HIV-1的潜伏机制提供重要线索。本项目利用高通量芯片筛选找到了与HIV-1复制及潜伏相关的lncRNA PSMD5-AS1，我们证实了lncRNA PSMD5-AS1参与了调控HIV-1的复制和潜伏。lncRNA PSMD5-AS1能抑制HIV-1的复制，同时也是维持HIV-1潜伏状态的重要分子；在机制上，我们发现lncRNA PSMD5-AS1对HIV-1的这一调控作用主要发生在病毒的转录环节，lncRNA PSMD5-AS1能够通过抑制HIV-1 LTR的转录活性来发挥抗病毒的作用，且这一调控作用是以不依赖于HIV-1转录激活因子Tat来发挥的，初步揭示了lncRNA PSMD5-AS1在调控HIV-1潜伏感染中的作用及分子机制。这将为阐明HIV-1潜伏机制提供新的线索，并为靶向治疗药物的开发进而达到HIV-1的功能性治愈提供理论依据。