Plug & Purge: In Vivo Targeting of Active HIV Reservoirs That Persist Despite ART

描述(由申请人提供)：了解艾滋病毒在抗逆转录病毒治疗中持续存在的机制是必要的，以便确定可能中断病毒传播的策略 坚持不懈，并最终导致根除病毒。在这方面，有两个重要的概念需要考虑。其一是存在一个长期存在的静止感染细胞的蓄水池，即使是生产性感染，在激活之前也不会产生病毒。这已被指定为潜在储集层，并已进行了广泛的调查。第二种是由高效感染的细胞组成，尽管抗逆转录病毒治疗，这些细胞继续以非常低的水平产生病毒。这已被指定为残留的活性艾滋病毒储存库，并是RFA-AI-12-042的主题。目前的提案是对这一RFA的回应。人们对活跃的艾滋病毒储存库，特别是血液中的艾滋病毒储存库进行了广泛的研究。相比之下，由于 从接受抗逆转录病毒治疗的感染患者身上获得足够的样本进行分析存在固有的困难。我们对组织中残留的活性艾滋病毒储存库知之甚少。因此，确实需要一种体内模型，在这种模型中，可以研究组织储存库，并可以评估旨在根除病毒的治疗干预措施。本实验室培育的骨髓-肝脏-胸腺(BLT)小鼠已被证实可用于研究HIV的潜伏期和持久性。当完成以下目标时，BLT小鼠在研究残留活性艾滋病毒储存库中的功能性和有用性将变得明显，其中将建立病毒持久性的参数，并将测试新的干预措施。我们项目的长期目标是开发和实施一个新的、可重复的和灵活的实验平台，在这个平台上可以评估消除残留的活跃艾滋病毒宿主的新方案，并直接比较它们的有效性。这将有助于告知哪些策略在人类身上实施时最有可能提供好处。具体目的1)鉴定在接受抗逆转录病毒治疗的HIV感染的BLT人源化小鼠的组织中存在的残留活性储存库。具体目的2)确定早期治疗对存在于不同组织中的活性HIV储存库的大小和分布的影响。具体目标3)建立一个平台，对旨在减少(或消除)残留的活跃艾滋病毒感染者的有针对性的干预措施进行评估。

DESCRIPTION (provided by applicant): Understanding the mechanisms by which HIV is able to persist in the face of ART is necessary in order to identify strategies that may interrupt viral persistence and ultimately lead to virus eradication. In this regard there are two important concepts to consider. One is the presence of a long-lasting reservoir of quiescent infected cells that even though productively infected do not produce virus until activated. This has been designated as the latent reservoir and has been the subject of extensive investigations. The second is composed of productively infected cells that continue to produce virus at very low levels despite ART. This has been designated as the residual active HIV reservoir and is the subject of RFA-AI-12-042. The current proposal is submitted in response to this RFA. The active HIV reservoir, particularly in the blood, has been extensively studied. In contrast, because of the intrinsic difficulties obtaining adequate samples for analysis from infected patients undergoing ART we know very little about the residual active HIV reservoir in tissues. Therefore there is a definitive need for an in vivo model where tissue reservoirs can be studied and where therapeutic interventions aimed at virus eradication can be evaluated. Bone marrow-liver-thymus (BLT) mice developed in our laboratory have been validated for the study of HIV latency and persistence. The functionality and usefulness of BLT mice in the study of the residual active HIV reservoir will become evident when the following aims are completed, wherein the parameters of viral persistence will be established and novel interventions will be tested. The long-term goal of our project is to develop and implement a novel, reproducible and flexible experimental platform in which novel protocols for eradication of the residual active HIV reservoir can be evaluated and directly compared for their efficacy. This will serve to inform which strategies have the best likelihood of providing benefit when implemented in humans. Specific Aim 1) To characterize the residual active reservoir present in the tissues of HIV infected BLT humanized mice undergoing ART. Specific Aim 2) To determine the effect of early treatment on the size and distribution of the active HIV reservoir present in different tissues. Specific Aim 3) To establish a platform for the evaluation of targeted interventions aimed at reducing (or eliminating) the residual active HIV reservoir.