Targeting HIV Myeloid Reservoirs in the CNS by IAP and TREM1 Inhibition

项目摘要 虽然联合抗逆转录病毒疗法（ART）已导致显着的艾滋病毒抑制和改善， 免疫功能，持久的病毒储库仍然是难治的强化抗病毒治疗。然而，在这方面， ART带来了许多挑战，如坚持药物治疗方案，出现耐药病毒， 长期治疗导致累积毒性。此外，这些病毒库直接或间接地 有助于病毒快速反弹，通常发生在停止ART后2周内。 ART是持续抑制病毒所必需的。因此，我们需要一种有效的方法， 一些新的影响深远的和不同的治疗方法， 目前正在调查解决这一问题的各种选择，其中最常见的是消除 持续性CD 4 + T细胞病毒库。然而，尽管潜伏感染的CD 4 + T细胞是主要的HIV感染者， 除了细胞库外，其他细胞类型，如巨噬细胞和小胶质细胞也是HIV持续存在的场所。这些 长寿命细胞对HIV的细胞病变效应具有抵抗力，并支持持续的容许HIV感染， 缺乏CD 4 + T细胞。此外，它们对CD 8 + T细胞介导的杀伤具有抗性。因此我们需要 一种有效的方法，也将消除艾滋病毒从这些病毒水库在个人的抑制性艺术。 然而，为了做到这一点，我们必须了解巨噬细胞和小胶质细胞如何抵抗病毒， 细胞病变我们的初步数据显示，巨噬细胞，在应对生产性艾滋病毒感染， 上调髓系细胞凋亡抑制蛋白（IAP）和触发受体的表达 cells-1（TREM 1），并且这些蛋白质的沉默或抑制会促进艾滋病毒感染者的选择性死亡 细胞而不增加病毒复制。这表明（i）IAP和TREM 1负责髓样细胞的增殖， 抗HIV细胞病变;和（ii）IAP和TREM 1代表消除HIV的新靶点。 因此，我们提出了一个创新的研究计划：（i）进行详细的机制研究，旨在 了解HIV感染的小胶质细胞如何抵抗病毒性细胞病变，重点是IAP和TREM 1;以及（ii） 确定利用这些发现逆转HIV耐药性和诱导HIV凋亡的新候选药物- 感染的小胶质细胞而不杀死未感染的小胶质细胞。因此，这些研究旨在寻找新的有效的 通过在ART中消除骨髓储库中的持续HIV感染来治愈HIV感染的方法， 治疗的病人。这种方法与针对病毒本身的传统策略有着根本的不同， 我们希望它能与ART互补。我们也希望这项工作的结果可以被翻译成 迅速采取旨在根除艾滋病毒感染的干预措施。

PROJECT SUMMARY Although combination antiretroviral therapy (ART) has led to significant HIV suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified antiviral therapy. However, ART poses many challenges such as adherence to drug regimens, the emergence of resistant virus, and cumulative toxicity as a result of long-term therapy. Moreover, these viral reservoirs directly or indirectly contribute to the rapid viral rebound that typically occurs within 2 weeks after cessation of ART. Thus, lifelong ART is required for continued viral suppression. Therefore, we need an effective approach that will eliminate HIV from viral reservoirs in individuals on suppressive ART. A number of novel far-reaching and varied therapeutic options are currently under investigation to address this concern, the most common of which is to eliminate the persistent CD4+ T cell viral reservoir. However, although latently infected CD4+ T cells are the predominant HIV reservoir, other cell types, such as macrophages and microglia also serve as sites of HIV persistence. These long-lived cells are resistance to the cytopathic effects of HIV and support persistent permissive HIV infection in the absence of CD4+ T cells. Moreover, they are resistant to CD8+ T cell-mediated killing. Therefore, we need an effective approach that will also eliminate HIV from these viral reservoirs in individuals on suppressive ART. However, in order to do this, it is essential that we understand how macrophage and microglia resist viral cytopathogenesis. Our preliminary data show that macrophages, in response to productive HIV infection, upregulate the expression of inhibitor of apoptosis proteins (IAPs) and triggering receptor expressed on myeloid cells-1 (TREM1), and that silencing or inhibition of these proteins promotes the selective death of HIV-infected cells without increasing viral replication. This suggests that (i) IAPs and TREM1 are responsible for myeloid cell resistance to HIV cytopathogenesis; and (ii) IAPs and TREM1 represent novel targets for the elimination of HIV. We therefore propose an innovative research program to: (i) conduct detailed mechanistic studies aimed at understanding how HIV-infected microglia resist viral cytopathogenesis with a focus on IAPs and TREM1; and (ii) identify new drug candidates that capitalize on these findings to reverse resistance and induce apoptosis of HIV- infected microglia without killing uninfected microglia. These studies are thus aimed at finding new effective approaches to curing HIV infection by eliminating persistent HIV infection from the myeloid reservoirs in ART- treated patients. This approach is fundamentally different from traditional strategies that target the virus itself, and we expect it to be complementary with ART. We also expect that the results from this work can be translated quickly into interventions aimed at eradicating HIV infection.