Targeting HIV Lung Reservoir in the Macaque Model

描述（由申请人提供）：尽管进行了HAART，HIV仍持续存在，并且停止HAART通常会导致病毒水平高反弹。因此，当务之急是识别并最终摧毁这些潜伏感染的病毒库。为了实现这一目标，明确识别潜伏期和 HAART 期间携带 HIV 的细胞和组织部位变得非常重要。我们的长期目标是抑制或防止HAART终止后病毒反弹。该 R21/R33 提案的目的是验证 CD4 T 细胞和巨噬细胞作为 SIV 感染、HAART 治疗恒河猴中储存细胞的贡献。我们的中心假设是，组织巨噬细胞（除了 CD4 T 细胞）充当主要病毒 (SIV) 储存库，最初在短寿命巨噬细胞中发育，然后转变为深层组织中寿命较长的巨噬细胞。第一阶段 (R21) 的目标是： 目标 1. 确定接受有效 HAART 的 SIV 感染猕猴中 CD4 T 细胞对 SIV 储库的贡献。我们的工作假设是，在接受有效HAART的SIV感染猕猴体内CD4细胞（通过抗CD4抗体）的耗竭将直接证明CD4 T细胞（相对于巨噬细胞）对SIV储存库的贡献比例。 目标 2. 确定接受有效 HAART 的 SIV 感染猕猴中单核细胞/巨噬细胞对储库的贡献。我们的工作假设是，接受有效HAART的感染SIV的猕猴体内单核细胞/巨噬细胞（通过脂质体阿仑膦酸盐）的消耗也将证明巨噬细胞（相对于CD4 T细胞）对SIV储存库的贡献。 这些研究以肺为模型，仔细检查“深层”组织中的 T 细胞和巨噬细胞库。这为第二阶段（R33）的确证研究奠定了基础，即现在检查HAART终止后的病毒储存库（即确定是否通过耗尽病毒储存库来防止病毒反弹，或者确定如果发生病毒反弹，病毒储存库仍然存在于何处）。 目标 3. 确定体内 CD4 和/或单核细胞/巨噬细胞的消耗是否可以防止 HAART 终止后病毒反弹。我们的工作假设是，CD4 T 细胞和巨噬细胞都有助于 SIV 储存库，并且在停止 HAART 后消除其中一个或两个细胞群将导致维持低病毒载量或没有病毒载量。相反，如果发生病毒反弹，我们将确定需要针对的病毒库的剩余或替代位点。总体结果将推动制定合理干预策略的工作，以抑制人类艾滋病的进展或治愈艾滋病。

DESCRIPTION (provided by applicant): HIV persists despite HAART, and discontinuation of HAART typically leads to high virus level rebound. A priority therefore is to identify and ultimately destroy these latently-infected virus reservoirs. To accomplish this, it becomes important to specifically identify the cells and tissue sites that harbor HIV during latency and HAART. Our long-term goal is to inhibit or prevent virus rebound after discontinuation of HAART. The purpose of this R21/R33 proposal is to verify the contributions of CD4+ T cells and macrophages as reservoir cells in SIV- infected, HAART-treated rhesus macaques. Our central hypothesis is that tissue macrophages (in addition to CD4+ T cells) serve as major virus (SIV) reservoirs that develop initially in short-lived macrophages and transi- tion to longer-lived macrophages in deep tissues. The aims of phase I (R21) are: Aim 1. To determine the contribution of CD4+ T cells to the SIV reservoir in SIV-infected macaques undergoing effective HAART. Our working hypothesis is that in vivo depletion of CD4 cells (via anti-CD4 antibody) in SIV-infected macaques undergoing effective HAART will directly demonstrate the proportion of CD4 T cells (vs macrophages) that contribute to the SIV reservoir. Aim 2. To determine the contribution of monocytes/macrophages to the reservoir in SIV-infected macaques undergoing effective HAART. Our working hypothesis is that the in vivo depletion of monocyte /macrophages (via liposome-alendronate) of the SIV-infected macaques undergoing effective HAART will also demonstrate a contribution of macrophages (vs CD4+ T cells) to the SIV reservoir. These studies focus on lung as a model to closely examine T cell and macrophage reservoirs in "deep" tis- sues. This sets the foundation for the corroborating studies of phase II (R33) to now examine viral reservoirs after discontinuation of HAART (i.e. to determine if viral rebound is prevented by having depleted the viral reservoirs or where viral reservoirs remain if virus rebound occurs). Aim 3. To determine if in vivo depletion of CD4 and/or monocyte/macrophages prevents virus rebound after discontinuation of HAART. Our working hypothesis is that both CD4+ T cells and macrophages con- tribute to SIV reservoirs and that elimination of either or both cell populations followed by discontinuation of HAART will lead to maintenance of low or absent viral load. Conversely, if virus rebound occurs, we will define the remaining or alternate sites of the virus reservoirs that need to be targeted. The overall results will move work forward to developing rational intervention strategies to inhibit progression or cure AIDS in humans.