The "Kick" Revisited in the "Kick and Kill" Strategy

“踢杀”策略中的“踢”重温

• 批准号: 9301475
• 负责人: NICOLAS PAUL SLUIS-CREMER
• 金额: $ 18.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301475
• 关键词: AKT Signaling Pathway; Address; Antigens; Apoptotic; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Death; Cell Survival; Cell model; Cells; Cessation of life; Clinical; Clinical Trials; DNA; Detection; Event; Exhibits; Goals; HIV; HIV Infections; HIV-1; Individual; Knowledge; Lead; Longevity; Memory; Pathway interactions; Patients; Pharmacology; Plasma; Proteins; RNA; Reaction Time; Rest; Source; T-Cell Activation; T-Cell Proliferation; Testing; Therapeutic; Viral; Viral Cytopathogenic Effect; Viral Proteins; Viremia; Virus; antiretroviral therapy; cytokine; insight; killings; macrophage; memory CD4 T lymphocyte; non-nucleoside reverse transcriptase inhibitors; novel; pol Gene Products; prevent; protein E; public health relevance; reactivation from latency; residence; small molecule

 DESCRIPTION (provided by applicant): Although combination antiretroviral therapy (cART) can reduce plasma HIV RNA levels in most infected individuals to below the detection limit of clinical assays, it is not curative and persistent viremia is detected in the majority of patients.A rare, but extremely stable, HIV proviral DNA reservoir in resting CD4+ T cells (i.e. the latent reservoir) is thought to be the major source of persistent viremia. This latent reservoir can produce infectious virus when the host cell is reactivated by recall antigen (or by various cytokines), that can reseed HIV infection if cART is discontinued. Eradication of the latent reservoir may lead to a cure for HIV infection. Currently, a "kick and kill" strategy is being testd in ongoing clinical trials as a pharmacological approach to deplete the latent HIV reservoir. This strategy involves the administration of a latency reversing agent (LRA) which induces HIV out of latency (the "kick"), that in turn facilitates death of the infected cells by viral cytopathic effets (the "kill"). Several distinct therapeutic classes of LRAs have been identified that effectively "kick" HIV out of latency. In contrast, our understanding of the "kill" in HIV-infected resting CD4 T cells is extremely limited. The primary goal of this study is to comprehensively assess the "kill in the "kick and kill" strategy, using novel primary cell models of latency in highly purified naïe (TN) and central memory (TCM) CD4+ T cells. Collectively, we anticipate that these studies will yield important insights into HIV persistence, and may have the potential to identify new targets or approaches to eradicate latent HIV infection. Furthermore, they could help explain clinical finding from ongoing trials that are focused on depleting the latent HIV reservoir.

 描述（申请人提供）：尽管联合抗逆转录病毒疗法（cART）可以将大多数感染个体中的血浆HIV RNA水平降低至低于临床测定的检测限，但它不是治愈性的，并且在大多数患者中检测到持续的病毒血症。静止CD4+ T细胞中的HIV前病毒DNA储库（即潜伏储库）被认为是持续性病毒血症的主要来源。当宿主细胞被召回抗原（或各种细胞因子）重新激活时，这种潜伏的储存库可以产生感染性病毒，如果cART中断，则可以重新接种HIV感染。根除潜伏的宿主可能导致治愈艾滋病毒感染。目前，正在进行的临床试验正在测试一种“踢杀”策略，作为一种耗尽潜伏的艾滋病毒储存库的药理学方法。该策略涉及施用潜伏期逆转剂（LRA），其诱导HIV脱离潜伏期（“踢”），这进而通过病毒致细胞病变效应促进受感染细胞的死亡（“杀死”）。已经确定了几种不同的LRA治疗类别，它们可以有效地将HIV“踢出”潜伏期。相比之下，我们对HIV感染的静息CD4 T细胞中的“杀伤”的理解非常有限。本研究的主要目标是使用高度纯化的naïe（TN）和中央记忆（TCM）CD4+ T细胞中潜伏期的新原代细胞模型，全面评估“踢杀”策略中的“杀死”。总的来说，我们预计这些研究将产生重要的见解艾滋病毒的持久性，并可能有潜力确定新的目标或方法，以消除潜伏的艾滋病毒感染。此外，它们可以帮助解释正在进行的试验中的临床发现，这些试验的重点是消除潜伏的HIV储存库。