HIV-1 Nef Interaction with Nef-associated Factor 1 Regulates Viral Latency

 描述（由申请人提供）：HIV-1致病因子Nef及其与宿主蛋白的相互作用对病毒发病机制很重要，但其在HIV-1潜伏期中的作用尚不清楚。Nef相关因子1（Naf 1），也称为A20结合NF-kB抑制剂（ABIN 1），是一种抑制NF-kB活化的宿主蛋白。NF-κ B是一种众所周知的HIV-1基因表达和病毒潜伏期的调节因子。有趣的是，我们的初步研究表明，Naf 1和Nef相互作用调节HIV-1基因转录和病毒潜伏期。我们发现（1）Naf 1抑制NF-kB依赖的HIV-1基因表达，Nef抵消了这种作用;（2）Naf 1通过抑制病毒基因转录维持HIV-1潜伏期，而Nef拮抗这种作用。因此，我们建议阐明Nef-Naf 1相互作用调节HIV-1潜伏期的机制，并寻求克服病毒潜伏期的新方法。我们的中心假设是（1）Naf 1通过抑制NF-κ B依赖的病毒基因转录来维持HIV-1潜伏期;（2）Nef通过诱导Naf 1磷酸化来拮抗Naf 1的抑制作用，这激活PI 3 K/Akt信号传导并导致HIV-1从潜伏期重新激活。我们提出了两个具体的目标来测试这些新的假设。目标1.探讨Naf 1-Nef相互作用调控HIV-1基因表达的机制。目标二。确定Naf 1和Nef相互作用在调节原代CD 4 + T细胞中HIV-1潜伏期中的功能。通过我们的合作努力完成拟议的研究将为调节HIV-1潜伏期的病毒和细胞机制提供新的见解。我们的预期结果将为靶向Nef-Naf 1相互作用和加强抗逆转录病毒治疗提供基础 HIV-1/AIDS的功能性治疗。

 DESCRIPTION (provided by applicant): The HIV-1 pathogenic factor Nef and its interactions with host proteins are important for viral pathogenesis, but their role in HIV-1 latency is not known. Nef-associated factor 1 (Naf1), also known as A20-binding inhibitor of NF-kB (ABIN1), is a host protein that inhibits NF-kB activation. NF-kB is a well-known regulator HIV-1 gene expression and viral latency. Intriguingly, our preliminary studies suggest that Naf1 and Nef interplay regulates HIV-1 gene transcription and viral latency. We found that (1) Naf1 suppresses NF-kB- dependent HIV-1 gene expression and Nef counteracts the effects; and (2) Naf1 maintains HIV-1 latency by suppressing viral gene transcription, while Nef antagonizes the effects. Therefore, we propose to delineate the mechanisms of Nef-Naf1 interactions in regulating HIV-1 latency and to seek a new approach to overcome viral latency. Our central hypotheses are (1) Naf1 maintains HIV-1 latency by suppressing NF- kB-dependent viral gene transcription; (2) Nef antagonizes the inhibitory effects of Naf1 by inducing Naf1 phosphorylation, which activates PI3K/Akt signaling and leads to HIV-1 reactivation from latency. We propose two specific aims to test these novel hypotheses. Aim 1. To investigate the mechanisms by which the Naf1-Nef interaction regulates HIV-1 gene expression. Aim 2. To determine the function of Naf1 and Nef interactions in modulating HIV-1 latency in primary CD4+ T cells. Accomplishing the proposed studies through our collaborative efforts will provide novel insights into the viral and cellular mechanisms of modulating HIV-1 latency. Our expected results will provide a basis to target Nef-Naf1 interactions and to enhance anti-retroviral therapy toward a functional cure for HIV-1/AIDS.