Prevention of HIV-induced T cell killing by autophagy

摘要 HIV的发病机制是由对病毒感染的非保护性炎症反应介导的。这是真的 HIV感染导致艾滋病的主要表现，CD4+T细胞耗尽，以及某些共同的 诸如过早衰老或神经变性等疾病仍然是艾滋病毒患者面临的挑战，尽管 通过抗逆转录病毒治疗抑制病毒。因此，除了限制病毒复制外，还需要 以抑制病毒感染引发的炎症级联反应。此应用程序的目的是测试 自噬，一种细胞废物管理途径，是否可以用来对抗艾滋病毒诱导的 发炎。自噬有可能通过两种方式保护人类免疫缺陷病毒。首先，自噬是 据报道，对包括艾滋病毒在内的几种病毒具有直接的抗病毒活性。第二，自噬可以 通过多种互补机制防止炎症过程。我们的假设是 自噬，当被现有的药物“启动”时，可以作为一种抗艾滋病毒的效应机制，也可以防止 HIV通过其抗炎活性诱导CD4+T细胞耗竭。 最近，由于改进了对炎症在HIV发病机制中的作用的理解，人们开始了解炎症的作用 艾滋病病毒感染的模型。虽然大多数艾滋病毒感染和炎症发生在体内的淋巴组织中， 大多数HIV感染的细胞培养模型使用细胞系或分离的血液来源免疫细胞。而这些 模型在许多方面都很有用，但它们不能代表复杂环境中发生的事情 淋巴组织。因此，我们将使用之前发表的淋巴组织体外模型，这将使我们能够 监测自噬诱导对HIV感染和传播以及炎性消耗的影响 在生理相关条件下对CD4+T细胞的影响。我们还将确定病毒或宿主因素 参与启动或传递对HIV的炎症反应是选择性自噬的目标，因为 可能是自噬发挥抗炎作用的一种机制。 这些目标的实现将：i)确定报告的自噬抗艾滋病毒行动是否在 生理上相关的感染模型，以及ii)评估自噬是否具有抗炎特性 可以对抗艾滋病毒引起的炎症和T细胞耗竭。这项工作可能导致实现或 加强自噬，在临床环境中减轻艾滋病毒的致病作用。我们在以下方面的专长 自噬和感染艾滋病毒将确保这些研究的成功结果。

SUMMARY HIV pathogenesis is mediated by non-protective inflammatory responses to viral infection. This is true of the primary manifestation of HIV infection that leads to AIDS, CD4+ T cell depletion, and also of certain co- morbidities such as premature aging or neurodegeneration that remain challenges for HIV patients in spite of viral suppression by antiretroviral therapy. As such, in addition to limiting viral replication, there is also a need to suppress the inflammatory cascade triggered by viral infection. The purpose of this application is to test whether autophagy, a cellular waste management pathway, could be engaged to counteract HIV-induced inflammation. Autophagy has the potential to protect against HIV pathogenesis in two ways. First, autophagy is reported to have direct antiviral activities against several viruses, including HIV. Second, autophagy can protect against inflammatory processes through multiple complimentary mechanisms. Our hypothesis is that autophagy, when “turned on” by existing drugs, can act as an anti-HIV effector mechanism and also prevent HIV-induced CD4+ T cell depletion through its anti-inflammatory activities. The understanding of inflammation’s role in HIV pathogenesis has emerged recently as a result of improved models of HIV infection. Whereas most HIV infection and inflammation takes place in lymphoid tissue in vivo, most cell culture models of HIV infection use cell lines or isolated blood-derived immune cells. While these models have been useful in many respects, they are not representative of what happens in the complex setting of lymphoid tissue. Thus, we will use a previously published ex vivo model of lymphoid tissue that will allow us to monitor the effect of autophagy induction on HIV infection and spread as well as the inflammatory depletion of CD4+ T cells under physiologically relevant conditions. We will also determine if viral or host factors implicated in initiating or transducing inflammatory responses to HIV are targets of selective autophagy as this would be one mechanism whereby autophagy could exert is anti-inflammatory effects. Completion of these aims will: i) determine if the reported anti-HIV actions of autophagy are active in a physiologically relevant model of infection, and ii) assess whether autophagy’s anti-inflammatory properties can counteract HIV-induced inflammation and T cell depletion. This work may lead to approaches to enable or enhance autophagy in ways that would mitigate HIV pathogenesis in a clinical setting. Our expertise in autophagy and in HIV will ensure a successful outcome of these studies.