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

 描述（由申请人提供）：本提案的实验旨在精确定义长期抗逆转录病毒治疗（ART）背景下HIV在何处以及如何持续存在。虽然通过采用有效的抗逆转录病毒疗法，艾滋病毒感染的影响已大大减少，但病毒并没有从宿主体内完全消除。相反，持续存在的病毒仍然以转录沉默的形式存在于淋巴和骨髓细胞的多个亚群中，这些亚群在外周循环和特定组织庇护所之间持续移动。我们的方法的基本原理是由以下观察结果所提示的，即持续性HIV的储存库似乎取决于相对于感染时间的ART开始的时间以及此后维持的时间。吉安现有的数据集，我们假设，窝藏艾滋病毒的细胞的星座是由中央和外周细胞稳态的生理机制，调节的稳态信号的复杂组合，包括白细胞介素7（IL-7）和15（IL-15），这是不同的ART启动和持续时间的功能。如果是这样的话，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的相互作用以及这些相互作用可能随时间和治疗持续时间而变化的方式来了解。在这项建议的实验中，我们打算研究调节潜伏HIV基因组的细胞内稳态的机制，以及有效ART的启动时间和持续时间如何影响HIV进入并持续存在于一些但不是所有亚群的倾向。本研究的目的有三：（1）评价ART治疗的起始时间和持续时间如何影响HIV病毒库的分布和组成;（2）评价体内携带HIV病毒的CD 4 + T细胞的更新和分化能力;（3）探讨IL-7和IL-15在HIV持久储库建立和维持中的作用。我们预计，这项研究产生的数据将提供新的见解艾滋病毒持续存在的机制，即使在ART的设置。在五年的时间内，我们应该能够明确说明是否启动时间和持续时间的ART决定的组成和营业额的持续艾滋病毒水库，从而确定了各种消除艾滋病毒的战略必须运作的环境。

 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.