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（由申请人提供）：虽然联合抗逆转录病毒疗法 (cART) 可以将大多数感染者的血浆 HIV RNA 水平降低至临床检测的检测限以下，但它并不能治愈，并且在大多数患者中检测到持续性病毒血症。但极其稳定的静息 CD4+ T 细胞中的 HIV 前病毒 DNA 库（即潜伏库）被认为是持续性病毒血症的主要来源，当宿主感染时，该潜伏库可产生感染性病毒。细胞被召回抗原（或各种细胞因子）重新激活，如果停止 cART，则可能重新传播 HIV 感染。目前，正在测试一种“踢杀”策略。正在进行的临床试验是一种消除潜伏艾滋病毒储存库的药理学方法，该策略涉及使用潜伏期逆转剂（LRA），该药物可诱导艾滋病毒脱离潜伏期（“踢”），从而促进死亡。已经确定了几种不同的 LRA 治疗类别，可以有效地将 HIV 排除在潜伏期之外，而我们对 HIV 感染的静息 CD4 的“杀死”的理解。 T 细胞极其有限，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 中的新型原代细胞潜伏期模型来全面评估“踢杀”策略中的“杀伤”。总的来说，我们预计这些研究将对艾滋病毒的持久性产生重要的见解，并且可能有可能确定消除潜在艾滋病毒感染的新目标或方法，此外，它们可以帮助解释正在进行的专注于消除艾滋病毒的临床发现。潜在的艾滋病毒储存库。