Mechanisms of Intrinsic Resistance to HIV Infection in Primary Human T Cells

原代人类 T 细胞对 HIV 感染的内在抵抗机制

基本信息

批准号：
7690840
负责人：
Derya Unutmaz
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2011-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We have identified a subset of CD4+ effector memory T cells (termed TEMRA cells) that are resistant to infection to CCR5-tropic (R5) HIV strains despite expressing high levels of cell surface CCR5. Remarkably, these cells are highly susceptible to HIV strains that enter cells via CXCR4 (X4-tropic). This peculiar subset is expanded in a portion of HIV-infected individuals and display relatively high CD4 cell numbers. The block to R5-tropic HIV infection in TEMRA cells is post-entry but prior to reverse transcription. These findings prompted us to better understand the mechanism of this unique intrinsic resistance mechanism in primary human T cells by pursuing the following aims: 1) Determine whether activation signals that can induce TEMRA-like cells from naive T cell subsets, which in turn become resistant to R5-tropic HIV infection. 2) Identify signals that can overcome the resistance of TEMRA cells. 3) Determine how TEMRA cells restrict HIV at the post-entry level. 4) Develop genetic screening approaches to identify potential intrinsic resistance factor(s) present in TEMRA cells. TEMRA cells serve as a tool for the identification of a novel means of host restriction. We believe the knowledge accrued from these studies is highly significant because identification of a novel intrinsic barrier to HIV infection can be: 1) Utilized to endow susceptible cells to be become resistant to infection; 2) Used to amplify vaccine approaches by inducing HIV resistant T cells; and 3) Harnessed to develop novel therapeutic approaches that take advantage of intrinsic host resistance in primary T cells. Our focus on the identification of a novel barrier to HIV infection within primary CD4+ T cells is an additional strength of the proposed studies and will provide a framework for future applications. PUBLIC HEALTH RELEVANCE: We identified a subset of human T cells that resist HIV infection. In this application we aim to identify the mechanism that restricts HIV infection in this human T cell substance. The knowledge gained from the proposed studies would be highly significant because they can help identify mechanisms that endow resistance to T cells in HIV-infected individuals, both during infection and in designing therapeutic vaccines.

描述（由申请人提供）：我们已经确定了CD4+效应的记忆T细胞（称为TEMRA细胞）的子集，该子集对CCR5-热带（R5）HIV菌株具有抗性，尽管表达了高水平的细胞表面CCR5。值得注意的是，这些细胞非常容易受到通过CXCR4（X4-Tropic）进入细胞的HIV菌株。该特殊的子集扩展在一部分HIV感染的个体中，并显示出相对较高的CD4细胞数量。 TEMRA细胞中R5授予HIV感染的阻滞是进入后的，但在逆转录之前。这些发现促使我们通过追求以下目的来更好地理解原代人T细胞中这种独特的内在抗性机制的机制：1）确定是否可以从天真T细胞子集中诱导Temra样细胞的激活信号，而Temra样细胞又对R5-纤维化HIV HIV感染具有抗性。 2）确定可以克服TEMRA细胞电阻的信号。 3）确定TEMRA细胞如何在入门后限制HIV。 4）开发遗传筛选方法，以鉴定TEMRA细胞中存在的潜在固有抗性因子。 Temra细胞是识别新型宿主限制方法的工具。我们认为，这些研究所产生的知识非常重要，因为对HIV感染的新内在障碍的鉴定可以：1）用于赋予易感细胞具有对感染具有抵抗力的易感性； 2）用于通过诱导抗HIV抗HIV T细胞来扩增疫苗方法； 3）利用新型的治疗方法，利用原代T细胞中固有的宿主抗性。我们专注于鉴定主要CD4+ T细胞中HIV感染的新型障碍，是拟议研究的附加优势，将为将来的应用提供框架。公共卫生相关性：我们确定了抗HIV感染的人类T细胞的一部分。在此应用中，我们旨在确定限制人类T细胞物质中HIV感染的机制。从拟议的研究中获得的知识将非常重要，因为它们可以帮助识别在感染期间和设计治疗疫苗中赋予HIV感染者中T细胞耐药性的机制。