Timing of ART and homeostasis of the persistent HIV reservoir in the adult

ART 的时机和成人持续性 HIV 病毒库的稳态

• 批准号: 8921906
• 负责人: JOSEPH M MCCUNE
• 金额: $ 76.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-04 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921906
• 关键词: Address; Adult; Affect; Blood Circulation; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Chronic; Clinical; Clinical Management; Complex; Data; Data Set; Disease; Effector Cell; Frequencies; General Hospitals; Goals; HIV; HIV Genome; HIV Infections; Homeostasis; Immune response; Immune system; Infection; Interleukin-7; Intervention; Kinetics; Knowledge; Label; Life; Longevity; Lymphoid Cell; Lymphopoiesis; Maintenance; Measures; Memory; Molds; Mus; Myeloid Cells; Nature; Outpatients; Peripheral; Physiological; Positioning Attribute; Production; Proliferating; Public Health; Recruitment Activity; Regulation; Relative (related person); Research Infrastructure; Role; San Francisco; Signal Transduction; Source; Stem cells; System; T memory cell; T-Lymphocyte; Thymus Gland; Time; Tissues; Viral; Virus; Water; Work; antiretroviral therapy; base; cohort; cytokine; in vivo; insight; integration site; progenitor; public health relevance; receptor; research study; treatment duration

 DESCRIPTION (provided by applicant): The experiments of this proposal intend to define precisely where and how HIV persists in the context of long-term antiretroviral therapy (ART). Although the impact of HIV infection has been substantially reduced by the introduction of effective ART, the virus is not completely eliminated from the host. Rather, persistent virus remains harbored in a transcriptionally silent form within multiple subpopulations of lymphoid and myeloid cells that are continuously moving between the peripheral circulation and specific tissue sanctuaries. The rationale for our approach is prompted by the observation that the reservoir of persistent HIV seems to vary depending on both the time when ART is started relative to the time of infection, and on the duration of time that it is thereafter maintained. Gien existing data sets, we hypothesize that the constellation of cells harboring HIV is formed in part by physiologic mechanisms of central and peripheral cell homeostasis, regulated by a complex combination of homeostatic signals including those provided by interleukin 7 (IL-7) and 15 (IL-15), which act differently as a function of ART initiation and duration. If so, then targeted interventions to eradicate HIV will be informed by further definition of the interactions that occu between the virus and various subpopulations of T and myeloid cells found in vivo, and of the way in which these interactions may change as a function of time and duration of treatment. In the experiments of this proposal, we intend to study the mechanisms that modulate the homeostasis of cells harboring latent HIV genomes, and how the timing of initiation and duration of effective ART impact upon the propensity of HIV to enter and persist in some but not all subpopulations. Experiments associated with three Specific Aims will be pursued: (1) to evaluate how the time of initiation and the duration of effective ART affect the distribution and composition of the persistent HIV reservoir; (2) to evaluate the turnover and differentiation capacity of CD4+ T cells harboring persistent HIV in vivo; and (3) to investigate the role of the c cytokines, IL-7 and IL-15, on the establishment and maintenance of the persistent HIV reservoir. We anticipate that the data generated by this study will provide new insights into the mechanisms by which HIV persists, even in the setting of ART. Within a five-year period of time, we should be in a position to definitively state whether or not the timing of initiation and duratin of ART dictate the composition and turnover of the persistent HIV reservoir, thereby defining the landscape on which various strategies to eradicate HIV must operate.

 描述（由申请人提供）：本提案的实验旨在准确定义艾滋病毒在长期抗逆转录病毒治疗（ART）背景下持续存在的位置和方式。尽管引入有效的抗逆转录病毒疗法已大大减少了艾滋病毒感染的影响，但病毒并未从宿主体内完全消除。相反，持久性病毒仍然以转录沉默的形式隐藏在淋巴和骨髓细胞的多个亚群中，这些细胞在外周循环和特定组织庇护所之间不断移动。我们的方法的基本原理是基于以下观察结果：持续性 HIV 储存库似乎会根据 ART 开始相对于感染时间的时间以及此后维持的持续时间而变化。根据现有的数据集，我们假设携带 HIV 的细胞群部分是由中枢和外周细胞稳态的生理机制形成的，受到复杂的稳态信号组合的调节，包括白细胞介素 7 (IL-7) 和 15 (IL-15) 提供的信号，这些信号根据 ART 启动和持续时间发挥不同的作用。如果是这样，那么根除艾滋病毒的有针对性的干预措施将通过进一步定义病毒与体内发现的各种T细胞和骨髓细胞亚群之间发生的相互作用，以及这些相互作用随着时间和治疗持续时间的变化而变化的方式来指导。在本提案的实验中，我们打算研究调节含有潜在 HIV 基因组的细胞稳态的机制，以及有效 ART 的开始时间和持续时间如何影响 HIV 进入并在某些但不是所有亚群中持续存在的倾向。将进行与三个具体目标相关的实验：（1）评估有效 ART 的开始时间和持续时间如何影响持续性 HIV 储存库的分布和组成； (2) 评价体内持续携带HIV的CD4+T细胞的周转和分化能力； (3) 研究 c 细胞因子 IL-7 和 IL-15 在持续性 HIV 储存库的建立和维持中的作用。我们预计，这项研究产生的数据将为 HIV 持续存在的机制提供新的见解，即使是在 ART 的情况下也是如此。在五年的时间内，我们应该能够明确说明抗逆转录病毒治疗的开始时间和持续时间是否决定了持久性艾滋病毒储存库的组成和周转，从而确定了各种根除艾滋病毒策略必须发挥作用的环境。