Targeting HIV Lung Reservoir in the Macaque Model

描述(由申请人提供)：尽管HAART，艾滋病毒仍然存在，停止HAART通常会导致高病毒水平反弹。因此，当务之急是识别并最终摧毁这些潜伏感染的病毒库。要做到这一点，在潜伏期和HAART期间明确识别携带艾滋病毒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停止后病毒反弹。R21/R33建议的目的是验证在SIV感染、HAART治疗的恒河猴中，CD4T细胞和巨噬细胞作为储藏细胞的贡献。我们的中心假设是，组织巨噬细胞(除CD4T细胞外)是主要的病毒(SIV)储存库，最初在短期的巨噬细胞中发育，并在深层组织中向长期的巨噬细胞转移。第一阶段(R21)的目标是： 目的1.确定SIV感染猕猴在接受有效的HAART治疗后，CD4T细胞对SIV储存库的贡献。我们的工作假设是，在接受有效的HAART治疗的SIV感染猕猴体内，CD4细胞的消耗(通过抗CD4抗体)将直接证明参与SIV储存库的CD4T细胞(与巨噬细胞)的比例。 目的2.在SIV感染的猕猴进行有效的HAART后，确定单核/巨噬细胞对贮存库的贡献。我们的工作假设是，在体内消耗SIV感染猕猴的单核/巨噬细胞(通过脂质体-阿伦磷酸钠)，并进行有效的HAART，也将证明巨噬细胞(VS CD4T细胞)对SIV储存库的贡献。 这些研究以肺为模型，密切观察“深层”组织中的T细胞和巨噬细胞储存库。这为第二阶段(R33)的确证研究奠定了基础，以便在HAART停止后现在检查病毒库(即确定是否通过耗尽病毒库来防止病毒反弹，或者如果病毒反弹发生，病毒库还留在哪里)。 目的3.确定体内CD4和/或单核/巨噬细胞的耗尽是否能阻止HAART停药后病毒的反弹。我们的工作假设是，CD4T细胞和巨噬细胞都属于SIV储存库，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不含病毒载量。相反，如果病毒反弹，我们将确定需要作为目标的病毒库的剩余或替代位置。总体结果将推动制定合理的干预策略，以抑制或治愈人类艾滋病的进展。

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.