Regulation of HIV by T-Cell Signal Transduction

T 细胞信号转导对 HIV 的调节

• 批准号: 7060900
• 负责人: Andrew J Henderson
• 金额: $ 27.79万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060900
• 关键词: CD28 molecule; T cell receptor; alkaline phosphatase; cell line; cell population study; chimeric proteins; clinical research; complementary DNA; genetic regulatory element; genetic transcription; host organism interaction; human immunodeficiency virus 1; human subject; leukocyte activation /transformation; molecular cloning; nucleic acid repetitive sequence; tissue /cell culture; transcription factor; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): T cell activation through the T cell receptor and costimulatory molecules such as CD28 has been demonstrated to influence the susceptibility of T cells to HIV-1 infection and regulate proviral transcription. However, the signaling events initiated by the T cell receptor complex and CD28 that /directly impact HIV-1 transcription have not been explored. In particular, it is unclear how CD28 signaling potentially enhances and inhibits HIV-1 expression. The objective this project is to determine the mechanisms by which CD28 regulates HIV-1 transcription, and to examine the interaction between HIV-1 Nef and CD28 signals. We hypothesize that CD28 engagement results in distinct signaling cascades that have very different consequences for HIV-1 expression and that the HIV-1 encoded protein Nef contributes to aberrant T cell signaling and function by interacting with different components of the CD28 signaling cascade. Our preliminary data using chimeric CD28 receptors that include mutations in critical tyrosine residues as well as inhibitors that block specific signal transduction pathways supports such a model. Furthermore, these initial experiments demonstrate phophatidylinositol-3-kinase inhibits H IV-1 transcription by a Tat-dependent mechanism. We are proposing to extend these studies and use cell lines, primary systems and biochemical approaches to 1) further characterize the role of differential signals from CD28 in regulating HIV-1 transcription, 2) characterize cis-elements and transcription factors that mediate induction of LTR activity in response to CD28 signals and 3) determine if Nef directly or indirectly alters CD28 signaling. Understanding the mechanisms by which CD28 regulates HIV-1 transcription will further define pathways associated with this receptor as well as identify putative upstream signal transduction events critical for controlling HIV-1 expression. Furthermore, the ability to manipulate these pathways may provide unique therapeutic targets for controlling virus expression. Relevance of this research to public health: We are proposing to identify and characterize cellular events that influence the production of HIV. Manipulating these cellular pathways may provide novel strategies that would complement current treatments to control HIV as well as approaches to purge latent HIV reserviors.

描述（由申请人提供）：已证明通过T细胞受体和共刺激分子（例如CD28）的T细胞激活会影响T细胞对HIV-1感染的敏感性并调节病毒的转录。但是，尚未探索由T细胞受体复合物和直接影响HIV-1转录的CD28引发的信号事件。特别是，尚不清楚CD28信号如何潜在地增强并抑制HIV-1表达。该项目的目的是确定CD28调节HIV-1转录的机制，并检查HIV-1 NEF和CD28信号之间的相互作用。我们假设CD28的参与导致不同的信号级联反应，这些级联对HIV-1表达产生截然不同的后果，并且HIV-1编码的蛋白质NEF通过与CD28信号级联的不同组件相互作用，从而有助于异常T细胞信号传导和功能。我们使用嵌合CD28受体的初步数据，其中包括关键酪氨酸残基中的突变以及阻止特定信号转导途径的抑制剂支持这种模型。此外，这些最初的实验表明磷脂酰肌醇-3-激酶通过TAT依赖性机制抑制H IV-1转录。我们提议将这些研究扩展并使用细胞系，主要系统和生化方法至1）进一步表征CD28中差分信号在调节HIV-1转录中的作用，2）表征介导LTR活性在CD28信号中介导LTR活性的表征和转录​​因子对CD28信号的响应和3）确定NEF是否直接或Dyf cd28 Signalters cd28 Signalsing。了解CD28调节HIV-1转录的机制将进一步定义与该受体相关的途径，并确定对控制HIV-1表达至关重要的推定上游信号转导事件。此外，操纵这些途径的能力可能会为控制病毒表达提供独特的治疗靶标。 这项研究与公共卫生的相关性：我们建议识别和表征影响艾滋病毒产生的细胞事件。操纵这些细胞途径可能会提供新的策略，以补充当前治疗以控制艾滋病毒 以及清除潜在艾滋病毒预防措施的方法。