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

 描述（由申请人提供）：该项目解决了关于 CD8 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 CD4 T 淋巴细胞的分化状态如何影响 CTL 杀伤的易感性。鉴于 CD4 T 淋巴细胞也含有细胞溶解机制，它们很可能与 CTL 具有类似的机制来保护自身免受细胞溶解，这可能有助于使它们产生抵抗力。细胞溶解蛋白酶的表达高度依赖于细胞分化/激活，HIV-1 蛋白表达也是如此。因此，尚不清楚这些对立因素如何相互平衡。我们探讨这些问题的目的是： 1. 评估负载表位或感染 HIV-1 的 CD4 T 淋巴细胞在不同分化/激活阶段对 CTL 杀伤的敏感性； 2. 评估 Nef 如何影响敏感性 不同分化阶段的CD4 T淋巴细胞对CTLs的抗病毒作用； 3. 探索增强CTL对杀伤能力相对抵抗的HIV-1感染的CD4 T淋巴细胞的杀伤策略。这些概念与理解HIV-1如何在普遍有效的CTL反应下持续存在高度相关，特别是受感染的细胞如何能够存活并从激活的效应器恢复到携带潜在储存库的静止记忆细胞，以及CTL如何有效地杀死受刺激以清除该储存库的受感染细胞，这些细胞被考虑用于治愈HIV-1感染的“休克和杀伤”策略。

 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.