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

• 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
• 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

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.

项目总结 尽管联合抗逆转录病毒疗法(ART)已导致艾滋病毒显著抑制和改善 免疫功能，持久的病毒库仍然是难以加强的抗病毒治疗。然而， 抗逆转录病毒疗法带来了许多挑战，如坚持药物治疗方案，出现耐药病毒，以及 长期治疗所致的累积毒性。此外，这些病毒库直接或间接地 有助于病毒的快速反弹，这种反弹通常发生在ART停止后的两周内。因此，终生 持续的病毒抑制需要抗逆转录病毒药物。因此，我们需要一种有效的方法来消除艾滋病毒。 从个人体内的病毒库对抑制艺术的影响。一批影响深远、多种多样的新奇疗法 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 持久的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 除了蓄水池外，其他类型的细胞，如巨噬细胞和小胶质细胞也是艾滋病毒持续存在的部位。这些 长寿命细胞对HIV的细胞病变效应具有抵抗力，并支持持续的允许HIV感染 缺乏CD4+T细胞。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 一种有效的方法，也将消除艾滋病毒从这些病毒储存库的个人对抑制性ART。 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是如何抵抗病毒的 细胞病理学。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时， 上调髓系细胞表达的凋亡抑制蛋白及其激活型受体 Cells-1(TREM1)，这些蛋白的沉默或抑制促进艾滋病毒感染者的选择性死亡 在不增加病毒复制的情况下。这表明：(1)IAPs和TREM1与髓系细胞有关 (2)IAP和TREM1是消除艾滋病毒的新目标。 因此，我们提出了一项创新的研究计划，以：(I)进行详细的机械研究，旨在 了解艾滋病毒感染的小胶质细胞如何抵抗病毒的细胞病变，重点是IAP和TREM1；以及(Ii) 找出利用这些发现逆转耐药性并诱导艾滋病毒凋亡的新药候选药物- 感染小胶质细胞而不杀死未感染的小胶质细胞。因此，这些研究的目的是找到新的有效方法 治疗艾滋病毒感染的方法，通过消除持续的艾滋病毒感染，从髓系储存库在ART- 治疗过的病人。这种方法从根本上不同于针对病毒本身的传统策略， 我们希望它能与艺术相辅相成。我们也期待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。