CD4 T Cell Differentiation and Susceptibility to HIV-Specific CTL Killing

CD4 T 细胞分化和对 HIV 特异性 CTL 杀伤的敏感性

• 批准号: 9065092
• 负责人: OTTO O YANG
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065092
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Retroviral Agents; Antiviral Agents; Apoptosis; Area; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Death; Cell Differentiation process; Cell Line; Cells; Cytolysis; Cytoplasmic Granules; Cytotoxic T-Lymphocytes; Data; Disease Progression; Down-Regulation; Enzymes; Epitopes; Equilibrium; Evolution; Granzyme; HIV; HIV-1; Immune; Immunotherapy; In Vitro; Infection; Killer Cells; Lymphocyte Subset; Mediating; Memory; Mutation; Outcome; Pathogenesis; Peptide Hydrolases; Persons; Predisposition; Production; Proteins; Resistance; Rest; Reverse Transcription; Role; Shock; Sorting - Cell Movement; Staging; Staining method; Stains; Survivors; T cell differentiation; Treatment Protocols; Viral; Virus Diseases; Virus Replication; annexin A5; cell injury; exhaustion; immortalized cell; killings; loss of function; perforin; protein expression; public health relevance; purge; response

 DESCRIPTION (provided by applicant): This project addresses a key question about the role of CD8+ cytotoxic T lymphocytes (CTLs) in HIV-1 pathogenesis, which is how the differentiation state of HIV-1-infected CD4+ T lymphocytes affects susceptibility to killing by CTLs. Given that CD4+ T lymphocytes also contain cytolytic machinery, it is likely that they have similar mechanisms to CTLs to protect themselves from cytolysis, which may help render them resistant. The expression of cytolytic proteases is highly dependent on cell differentiation/activation, as is HIV-1 protein expression. It is therefore unclear how these opposing factors balance each other. Our aims to explore these issues are: 1. To assess the susceptibility of epitope-loaded or HIV-1-infected CD4+ T lymphocytes in different stages of differentiation/activation to killing by CTLs; 2. To evaluate how Nef affects the susceptibility of CD4+ T lymphocytes in different stages of differentiation to the antiviral effects of CTLs; 3. To explore strategies to enhance CTL killing of HIV-1-infected CD4+ T lymphocytes that are relatively resistant to killing. These concepts are highly relevant to understanding how HIV-1 persists in the face of a generally potent CTL response, especially how infected cells can survive to revert from activated effectors to resting memory cells bearing the latent reservoir, and how well CTLs would kill infected cells that are stimulated to purge this reservoir in "shock and kill" strategies being considered for cure of HIV-1 infection.

 描述（由申请人提供）：本项目解决了关于CD 8+细胞毒性T淋巴细胞（CTL）在HIV-1发病机制中的作用的关键问题，即HIV-1感染的CD 4 + T淋巴细胞的分化状态如何影响CTL杀伤的易感性。鉴于CD 4 + T淋巴细胞也含有细胞溶解机制，它们可能具有与CTL相似的机制来保护自身免受细胞溶解，这可能有助于使它们具有抗性。溶细胞蛋白酶的表达高度依赖于细胞分化/活化，HIV-1蛋白表达也是如此。因此，不清楚这些对立的因素如何相互平衡。我们探讨这些问题的目的是：1。评估负载表位或HIV-1感染的CD 4 + T淋巴细胞在不同分化/活化阶段对CTL杀伤的敏感性; 2.为了评估Nef如何影响 CD 4 + T淋巴细胞在不同分化阶段对CTLs的抗病毒作用; 3.探索增强对杀伤相对抵抗的HIV-1感染的CD 4 + T淋巴细胞的CTL杀伤的策略。这些概念与理解HIV-1如何在面对通常有效的CTL应答时持续存在高度相关，特别是感染的细胞如何能够存活以从活化的效应子恢复到携带潜伏储库的静息记忆细胞，以及CTL将如何杀死被刺激以在考虑用于治愈HIV-1感染的“休克和杀死”策略中清除该储库的感染细胞。