Role of PACS-1 in HIV-1 Immunoevasion

描述(由申请人提供)：全球艾滋病疫情继续 愤怒，有4000万人感染艾滋病毒-1或因艾滋病而虚弱。 对HIV-1感染者的分析和动物模型研究表明 艾滋病的快速发病需要HIV-1蛋白Nef的表达。这 慢病毒蛋白在艾滋病的病理生理学中具有多种作用，包括 感染细胞中宿主CD4和MHC-1分子的下调。这个 CD4的下调消除了病毒受体对HIV-1的干扰 包膜和MHC-1下调使病毒能够逃避免疫 监控系统。尽管Nef介导的下调调控的重要性 MHC-1与艾滋病的发展有关，关于细胞和 控制这一过程的生化途径。最近，这个实验室 报道了细胞蛋白质PACS-1的鉴定，他们认为 控制Nef介导的MHC-1下调。他们显示PACS-1与 HIV-1Nef在细胞内形成蛋白质复合体。此外，HIV-1 Nef需要 PACS-1通过重新分配这种免疫来特异性下调MHC-1 监视分子连接到跨高尔基网络。身份的识别 Pacs-1/Nef复合体提供了对这一机制的一些初步见解 HIV-1介导的MHC-1分子下调。建议的研究首先 将确定HIV-1关联所需的结构性决定因素 NEF和PACS-1，并阐明PACS-1/Nef复合体的形成 受监管的。其次，他们将确定PACS-1/Nef使用的细胞途径 将MHC-1隔离在跨高尔基网络中。第三，他们将测试 PACS-1/Nef复合体成为潜在药理靶点的可能性 因为扰乱了HIV-1免疫逃避。总之，这些研究将增加我们的 了解HIV-1的生化和细胞基础S逃避病毒的能力 免疫监视系统，以及提供对 阻断这一过程的药理策略。

DESCRIPTION (provided by the applicant): The global AIDS epidemic continues to rage, with 40 million people infected with HIV-1 or debilitated by AIDS. Analysis of HIV-1 infected individuals and studies in animal models show the rapid onset of AIDS requires expression of the HIV-1 protein Nef. This lentivirus protein has manifold roles in the pathophysiology of AIDS, including the downregulation of the host CD4 and MHC-1 molecules in infected cells. The downregulation of CD4 eliminates interference of the viral receptor with HIV-1 envelopment and MHC-1 downregulation enables the virus to evade the immune surveillance system. Despite the importance of Nef-mediated downregulation of MHC-1 to the development of AIDS, little is known regarding the cellular and biochemical pathways that control this process. Recently, this laboratory reported the identification of the cellular protein, PACS-1, that they believe controls the Nef-mediated downregulation of MHC-1. They showed PACS-1 binds to HIV-1 Nef to form a protein complex in cells. Moreover, HIV-1 Nef requires PACS-1 to specifically downregulate MHC-1 by redistributing this immune surveillance molecule to the trans-Golgi network. The identification of the PACS-1/Nef complex has provided some of the first insights into the mechanism of HIV-1-mediated downregulation of MHC-1 molecules. The proposed studies first will identify the structural determinants required for the association of HIV-1 Nef and PACS-1 and elucidate how formation of the PACS-1/Nef complex is regulated. Second, they will identify the cellular pathway used by PACS-1/Nef to sequester MHC-1 in the trans-Golgi network. Third, they will test the possibility that the PACS-1/Nef complex is a potential pharmacological target for disrupting HIV-1 immune evasion. Together, these studies will increase our knowledge of the biochemical and cellular basis of HIV-1's ability to evade the immune surveillance system, as well as provide new insights into pharmacological strategies to block this process.