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（通过应用提供）：尽管抗逆转录病毒疗法（CART）可以将大多数感染个体的血浆HIV RNA水平降低到低于临床评估的检测限制，但在大多数患者中却没有治愈，并且在大多数患者中检测到持续性病毒性。持续的病毒血症。当宿主细胞被召回抗原（或各种细胞因子）重新激活时，该潜在储层会产生传染性病毒，如果停用了CART，则可以恢复HIV感染。消除潜在储层可能会导致治愈HIV感染。目前，正在进行的临床试验中，正在对“踢和杀戮”策略进行测试，以此作为耗尽潜在艾滋病毒水库的药物方法。该策略涉及延迟逆转剂（LRA）的给药，该潜伏期逆转剂（LRA）从潜伏期中诱导艾滋病毒（“踢”），进而促进了受病毒细胞病毒效应（“杀死”）的感染细胞死亡。已经确定了几种不同的LRA治疗类别，它们从潜伏期中有效地“踢”了HIV。相反，我们对HIV感染的静止CD4 T细胞中“杀死”的理解非常有限。这项研究的主要目标是全面评估“踢和杀死”策略中的“杀死”，使用高度纯化的幼稚（TN）和中央记忆（TCM）CD4+ T细胞中的新型主要细胞模型，我们共同预计，这些研究将产生对HIV持续性的重要见解，并可能通过启用HIV的启发性地进行启发，从而识别出新的目标，从而降低了辐射效率。旨在耗尽潜在艾滋病毒水库的试验。