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

 描述(申请人提供)：这个项目解决了CD8细胞毒性T淋巴细胞(CTL)在HIV-1发病机制中的作用的一个关键问题，即HIV-1感染的CD4T淋巴细胞的分化状态如何影响CTL杀伤的敏感性。鉴于CD4T淋巴细胞也含有细胞溶解机制，它们很可能具有与CTL相似的机制来保护自己免受细胞溶解的影响，这可能有助于使它们具有抵抗力。细胞溶解蛋白的表达高度依赖于细胞的分化/激活，HIV-1蛋白的表达也是如此。因此，目前尚不清楚这些对立因素是如何相互平衡的。我们的目标是：1.评估表位负载或HIV-1感染的CD4T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CTL的敏感性 CD4T淋巴细胞在不同分化阶段对CTL的抗病毒作用；3.探讨增强CTL杀伤HIV-1感染后相对耐药的CD4T淋巴细胞的策略。这些概念与理解HIV-1如何在普遍有效的CTL反应面前持续存在高度相关，特别是受感染的细胞如何存活，从激活的效应器恢复到携带潜伏库的静止记忆细胞，以及CTL如何很好地杀死受感染的细胞，这些细胞受到刺激以清除这个库正在考虑的治疗艾滋病毒-1感染的“休克和杀死”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.