CD163 in HIV Immunopathogenesis

CD163 在 HIV 免疫发病机制中的作用

• 批准号: 8601783
• 负责人: Steven Daniel Douglas
• 金额: $ 23.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-13 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601783
• 关键词: AIDS neuropathy; Address; Affect; Agonist; Amino Acids; Antibodies; Binding; Biological; Cell Separation; Cells; Data; Development; Disease; Event; Goals; Grant; HIV; HIV Infections; HIV Receptors; HIV Seropositivity; HIV therapy; HIV-1; Haptoglobins; Hemoglobin; Human; In Vitro; Individual; Infection; Investigation; Link; Liquid substance; Maintenance; Mediating; Membrane; Methods; Neurocognitive; Pathogenesis; Phase; Phenotype; Play; Population; Productivity; Regulation; Role; SIV; Series; Signal Transduction; Small Interfering RNA; Substance P; Substance P Receptor; T-Cell Proliferation; T-Lymphocyte; Tachykinin; Tissues; Transfection; Up-Regulation; Viral; Work; base; design; extracellular; macrophage; monocyte; novel; public health relevance; receptor; receptor binding; research study; scavenger receptor

DESCRIPTION (provided by applicant): Macrophages play a significant role in HIV-1, in both productive infection and maintenance of the viral reservoir. While the current efforts of eradication of HIV are mostly directed toward latently infected T-cells, macrophages are largely ignored. Macrophages are however likely to contribute to maintenance of the viral reservoir especially in the CNS where HIV infection is often associated with CD163 positive macrophages. Our previous work has demonstrated that substance P (SP), the endogenous neurokinin 1 receptor (NK1R) agonist, promotes HIV infection in macrophages, whereas treatment of macrophages with NK1R antagonists inhibits HIV infection. During the course of our current investigations, we made a novel observation which is the basis of this R21 grant; the treatment of human macrophages with SP ex vivo increases levels of both soluble and membrane bound forms of CD163, the scavenger receptor for haptoglobin-hemoglobin. CD163 is a marker which is uniquely expressed on cells of monocyte-macrophage origin and present in biological fluids in a stable soluble form (sCD163). Significant evidence has been accumulated demonstrating increases in CD163 levels in HIV infected individuals, however, the direct involvement of this molecule in HIV pathogenesis is unknown. Using two independent methods, cell sorting and siRNA, we demonstrated that higher levels of membrane bound CD163 are associated with higher HIV infection in macrophages. In the next phase of our investigations, we have designed a series of novel experiments in order to establish the roles of soluble and membrane-bound CD163 in HIV infection (Aims 1 and 2), and to determine if SP-induced enhancement of HIV infection is related to NK1R-mediated regulation of CD163 expression in human monocytes-macrophages (Aim 3). This R21 focuses on the mechanisms of HIV infection in macrophages and has direct implications for development of novel HIV therapies.

描述（由申请人提供）： 巨噬细胞在HIV-1中起着重要作用，在病毒储层的生产性感染和维持中。虽然目前消除艾滋病毒的努力主要针对潜在感染的T细胞，但巨噬细胞在很大程度上被忽略了。但是，巨噬细胞可能有助于维持病毒储存库，特别是在CNS中，HIV感染通常与CD163阳性巨噬细胞相关。我们以前的工作表明，内源性神经蛋白1受体（NK1R）激动剂P（SP）促进巨噬细胞中的HIV感染，而NK1R拮抗剂抑制HIV感染的巨噬细胞。在目前的调查过程中，我们进行了一种新颖的观察，这是R21赠款的基础。用SP的治疗人类巨噬细胞的治疗增加了CD163的可溶性和膜结合形式的水平。 CD163是一种标记物，在单核细胞巨噬细胞起源的细胞上唯一表达，并以稳定的可溶性形式（SCD163）以生物流体形式存在。已经积累了大量证据，证明艾滋病毒感染个体的CD163水平增加，但是，该分子在HIV发病机理中的直接参与尚不清楚。使用两种独立的方法，即细胞分类和siRNA，我们证明了较高水平的膜结合的CD163与巨噬细胞中较高的HIV感染有关。在我们的下一阶段，我们设计了一系列新型实验，以确定可溶性和膜结合的CD163在HIV感染中的作用（AIMS 1和2），并确定SP诱导的HIV感染增强是否与NK1R介导的NK1R介导的CD163在人类单局元中的表达相关（AIM-MACR型3）。该R21侧重于巨噬细胞中HIV感染的机制，并直接对新型HIV疗法的发展产生影响。