Targeting HIV Lung Reservoir in the Macaque Model

描述（由申请人提供）：尽管HAART治疗，HIV仍然存在，停止HAART治疗通常会导致高病毒水平反弹。因此，当务之急是确定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的细胞和组织位点变得非常重要。我们的长期目标是抑制或防止HAART停药后病毒反弹。这项R21/R33提案的目的是验证CD4+ T细胞和巨噬细胞在SIV感染、haart治疗的恒河猴体内作为储库细胞的作用。我们的中心假设是，组织巨噬细胞（除了CD4+ T细胞外）作为主要的病毒（SIV）储存库，最初在短寿命巨噬细胞中发展，并过渡到深部组织的较长寿命巨噬细胞。第一阶段（R21）的目标是：

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.