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

通过 IAP 和 TREM1 抑制靶向 CNS 中的 HIV 骨髓库

基本信息

批准号：
10747040
负责人：
Grant R Campbell
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747040
关键词：
Address Adherence Antiviral Therapy Apoptosis Apoptotic Autophagocytosis BCL2 gene BCL2L1 gene BCL2L11 gene BIRC2 gene BIRC4 gene Blood Vessels CASP8 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Death Induction Cell Survival Cells Cessation of life Data Development Dose Goals HIV HIV Antigens HIV Envelope Protein gp120 HIV Infections HIV Long Terminal Repeat HIV resistance HIV-1 Human Immune Evasion Immunologic Deficiency Syndromes Individual Induction of Apoptosis Infection Intervention Investigation Macrophage Mediating Membrane Potentials Microglia Modeling Myelogenous Myeloid Cells Neurons Patients Peptides Pharmaceutical Preparations Phenotype Process Productivity Proteins RNA Refractory Regimen Research Resistance Rest Risk Role Site Source TNF gene Testing Therapeutic Toxic effect Translating Up-Regulation Viral Viral reservoir Virus Virus Replication Work antagonist antiretroviral therapy base cell type design drug candidate high reward immune function improved inhibitor inhibitor-of-apoptosis protein innovation mimetics mitochondrial membrane novel novel therapeutic intervention novel therapeutics permissiveness pharmacologic programs receptor response viral rebound

项目摘要

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.

项目概要尽管联合抗逆转录病毒疗法 (ART) 已显着抑制 HIV 并改善免疫功能，持续的病毒储存库仍然存在，对强化抗病毒治疗无效。然而， ART 带来了许多挑战，例如遵守药物治疗方案、耐药病毒的出现以及长期治疗导致的累积毒性。此外，这些病毒储存库直接或间接导致病毒快速反弹，通常发生在停止 ART 后 2 周内。于是，终生持续抑制病毒需要 ART。因此，我们需要一种有效的方法来消除艾滋病毒来自接受抑制性 ART 的个体的病毒储存库。一系列新颖、深远、多样的治疗方法目前正在研究解决这一问题的方案，其中最常见的是消除持久性 CD4+ T 细胞病毒库。然而，尽管潜伏感染的 CD4+ T 细胞是主要的 HIV 除了储存库之外，其他细胞类型，例如巨噬细胞和小胶质细胞，也可以作为艾滋病毒持续存在的场所。这些长寿细胞能够抵抗 HIV 的细胞病变效应，并支持持续允许的 HIV 感染 CD4+ T 细胞的缺失。此外，它们对 CD8+ T 细胞介导的杀伤具有抵抗力。因此，我们需要这是一种有效的方法，可以消除接受抑制性抗逆转录病毒疗法的个体中这些病毒库中的艾滋病毒。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理发生。我们的初步数据表明，巨噬细胞响应生产性艾滋病毒感染，上调凋亡蛋白抑制剂 (IAP) 的表达和骨髓表达的触发受体 cells-1 (TREM1)，沉默或抑制这些蛋白质会促进 HIV 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 TREM1 负责骨髓细胞对 HIV 细胞病变的抵抗； (ii) IAP 和 TREM1 代表了消除 HIV 的新目标。因此，我们提出一项创新研究计划：(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细胞病变，重点关注 IAP 和 TREM1； (二) 确定新的候选药物，利用这些发现来逆转耐药性并诱导 HIV 细胞凋亡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方法通过消除 ART 中骨髓库中持续的 HIV 感染来治愈 HIV 感染的方法- 接受治疗的患者。这种方法与针对病毒本身的传统策略有根本不同，我们希望它能够与 ART 形成互补。我们还期望这项工作的成果能够被转化迅速采取旨在根除艾滋病毒感染的干预措施。