Molecular Mechanisms of the Innate Immune Response in HIV-Infected Macrophages

HIV感染巨噬细胞先天免疫反应的分子机制

• 批准号: 9512029
• 负责人: Kathleen L. Collins
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-17 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9512029
• 关键词: Alleles; Alpha Cell; Amination; Amines; Antibody Response; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antiviral Agents; Binding; Binding Proteins; Biological Models; Blood; Bone Marrow; Cell Line; Cells; Characteristics; Data; Development; Disease; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Immune response; Immune system; Immunologics; Individual; Infection; Innate Immune Response; Knowledge; Laboratories; Link; Lung; Lymph Node Tissue; Mannose; Maps; Mediating; Mission; Modeling; Molecular; Myeloid Cells; Pathway interactions; Patients; Phagocytosis; Phenotype; Population; Predisposition; Proteins; Psyche structure; Public Health; Research; Resistance; Role; SIV; Sampling; Site; Societies; System; T-Lymphocyte; Testing; Tonsil; Tonsillar Tissue; United States National Institutes of Health; Viral; Viral Load result; Virion; Virus; Virus Diseases; Work; antiretroviral therapy; base; env Gene Products; experience; glycosylation; in vivo; macrophage; mannose receptor; monocyte; novel strategies; pathogen; receptor binding; transmission process; virus characteristic

Our laboratory’s long-range goal is to understand how HIV-1 persists despite optimal antiretroviral therapy and to develop new approaches to clear the infection. Virus isolated from patient blood encodes vpr, which is packaged into virions and expressed at late stages of viral infection. Vpr is needed for optimal infection of macrophages, tonsillar tissue and SIV model systems, however its actions in T cells are largely detrimental to infection and a requirement for Vpr for HIV infection is not observed in pure T cell systems. There is currently a critical gap in our understanding of why Vpr is conserved in the virus despite its unique role in macrophages, which are not known to be crucial for HIV transmission or persistence. Our preliminary data strongly indicate that Vpr is responsible for downmodulation of a macrophage-specific protein that interferes with Env expression. Thus, the objectives of this application are (1) to determine the extent to which Vpr-mediated downmodulation of the macrophage protein alleviates restriction of Env and spread of HIV in macrophages, (2) to determine the domain of Env required for restriction in macrophages and (3) to identify viral populations from in vivo samples that manifest these phenotypes. Our central hypothesis is that a macrophage protein binds residues on Env and targets it to degradative and/or antigen presentation compartments to restrict spread and enhance antigen presentation in infected and bystander myeloid cells; Vpr counteracts this pathway by reducing levels of the restricting protein through direct infection and fusion of Vpr-containing virions with bystander myeloid cells. The rationale for the proposed work is that a greater understanding of how HIV overcomes cellular antiviral mechanisms to establish a persistent infection in macrophages will facilitate efforts to clear infection in the CNS and other reservoirs. Thus, we plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: 1. Determine the extent to which the macrophage protein we have identified accounts for restriction of Env in HIV infected macrophages lacking Vpr. 2. Define the domain of Env proteins needed for susceptibility to restriction by macrophages. 3. Identify viral populations from in vivo samples that target the restriction factor. At the completion of these studies we expect to determine the extent to which; (1) macrophages restrict viral infection by targeting a specific domain on Env, (2) sensitivity to this restriction is an important characteristic of viruses that form reservoirs in people, (3) Vpr functions to counteract this restriction by downmodulating the macrophage protein. An understanding of the macrophage restriction factor and identification of Env domains responsible for sensitivity to the restriction may provide new approaches to limit spread of HIV and enhance the immune response by promoting antigen presentation. Targeting the mechanisms by which the virus disrupts the immune system may allow the development of safer, more specific treatment approaches that will promote the clearance of HIV-1 infected cells.

我们实验室的远程目标是了解HIV-1如何持续dospite最佳抗逆转录病毒疗法 并开发新的方法来清除感染。从患者血液中分离的病毒编码VPR，这是 包装成病毒，并在病毒感染的后期表达。最佳感染需要VPR 巨噬细胞，扁桃体组织和SIV模型系统，但是其在T细胞中的作用在很大程度上有害 在纯T细胞系统中未观察到感染和对HIV感染的VPR的需求。目前有 我们了解为什么VPR在病毒目的地保存其在巨噬细胞中的独特作用的关键差距， 对于HIV传播或持久性而言，这不是至关重要的。我们的初步数据强烈表明 该VPR负责下调巨噬细胞特异性蛋白，该蛋白会干扰Env 表达。那就是（1）确定VPR介导的程度（1） 巨噬细胞蛋白的下调减轻了巨噬细胞中ENV和HIV的限制，（2） 确定巨噬细胞限制所需的Env领域，以及（3）从 体内样品表现出这些表型。我们的中心假设是巨噬细胞蛋白结合 Env上的残留物，并将其针对降解和/或抗原演示室以限制传播和 增强感染和旁观者髓样细胞中的抗原表现； VPR通过 通过直接感染和富含VPR的病毒融合的限制蛋白质的水平 旁观者髓样细胞。拟议工作的理由是，对艾滋病毒的方式有了更大的了解 克服细胞抗病毒机制以在巨噬细胞中建立持续感染将有助于努力 清除中枢神经系统和其他水库中的感染。这，我们计划检验我们的中心假设并完成 通过追求以下特定目标：1。确定该应用程序的目的 巨噬细胞蛋白我们已经确定了缺乏HIV感染的巨噬细胞中ENV的限制 vpr。 2。定义对巨噬细胞限制易感性所需的ENV蛋白的结构域。 3。识别 来自靶向限制因子的体内样品的病毒群体。完成这些研究时，我们 期望确定多大程度上； （1）巨噬细胞通过靶向特定域来限制病毒感染 在Env上，（2）对这一限制的敏感性是形成人们中储层的病毒的重要特征， （3）VPR功能通过下调巨噬细胞蛋白来抵消这种限制。对 巨噬细胞限制因素和对限制敏感性的ENV域的识别 可以提供新的方法来限制艾滋病毒的传播并通过促进抗原增强免疫反应 推介会。针对病毒破坏免疫系统的机制可能允许 开发更安全，更具体的治疗方法，以促进被感染HIV-1的清除 细胞。