Targeting HIV Lung Reservoir in the Macaque Model

在猕猴模型中针对 HIV 肺储库

• 批准号: 8656273
• 负责人: Marcelo J Kuroda
• 金额: $ 22.27万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656273
• 关键词: Achievement; Alendronate; Alveolar Macrophages; Animal Model; Antibodies; Bacteriophages; CD4 Positive T Lymphocytes; Cells; Controlled Study; DNA; Development; Disease; Disease Progression; Encapsulated; Foundations; Genome; Goals; HIV; Highly Active Antiretroviral Therapy; Human; Individual; Infection; Injection of therapeutic agent; Intervention; Lead; Life; Liposomes; Lung; Macaca; Macaca mulatta; Maintenance; Measures; Modeling; Natural Immunity; Outcome; Pathogenesis; Patients; Phase; Play; Population; Positioning Attribute; Primates; RNA; Research; Rest; Role; SIV; Site; Specimen; Structure of parenchyma of lung; Syndrome; T memory cell; T-Lymphocyte; Terminal Disease; Tissues; Toxic effect; Viral; Viral Load result; Virus; Virus Diseases; Virus Latency; Work; acquired immunodeficiency; defined contribution; experience; in vivo; in vivo Model; interest; interstitial; lung basal segment; macrophage; memory CD4 T lymphocyte; monocyte; nonhuman primate; phase 2 study; prevent; public health relevance; research study; viral DNA

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.

描述（由申请人提供）：尽管HAART，HIV仍然存在，HAART的中止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在感染的病毒宿主。为了实现这一点，重要的是要明确识别潜伏期和HAART期间携带HIV的细胞和组织部位。我们的长期目标是抑制或预防HAART停药后病毒反弹。该R21/R33提案的目的是验证CD 4 + T细胞和巨噬细胞作为SIV感染的HAART处理的恒河猴中的储库细胞的贡献。我们的中心假设是，组织巨噬细胞（除CD 4 + T细胞外）作为主要病毒（SIV）储库，最初在短寿命巨噬细胞中发育，并在深层组织中过渡为长寿命巨噬细胞。第一阶段（R21）的目标是： 目标1.在接受有效HAART的SIV感染猕猴中，确定CD 4 + 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感染的猕猴中，体内CD 4细胞（通过抗CD 4抗体）的耗竭将直接证明有助于SIV储库的CD 4 T细胞（与巨噬细胞）的比例。 目标2.确定单核细胞/巨噬细胞对接受有效HAART的SIV感染猕猴中储库的贡献。我们的工作假设是，在体内消耗单核细胞/巨噬细胞（通过脂质体-阿仑膦酸钠）的SIV感染的猕猴进行有效的HAART也将证明巨噬细胞（相对于CD 4 + T细胞）的SIV水库的贡献。 这些研究集中于肺作为密切检查“深部”组织中T细胞和巨噬细胞储库的模型。这为II期（R33）的确证性研究奠定了基础，现在可以检查HAART停药后的病毒储库（即，确定是否通过耗尽病毒储库来预防病毒反弹，或者如果发生病毒反弹，病毒储库仍然存在）。 目标3.确定体内清除CD 4和/或单核细胞/巨噬细胞是否可预防HAART停药后病毒反弹。我们的工作假设是，CD 4 + T细胞和巨噬细胞都有助于SIV储库，并且在HAART停止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存在病毒载量。相反，如果发生病毒反弹，我们将确定需要靶向的病毒宿主的剩余或替代位点。总体结果将推动工作向前发展，以制定合理的干预战略，以抑制进展或治愈艾滋病的人类。