The role of myeloid cells in viral replication, persistence and neuroinvasion

骨髓细胞在病毒复制、持久性和神经侵袭中的作用

• 批准号: 8071784
• 负责人: Mario Stevenson
• 金额: $ 38.41万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071784
• 关键词: AIDS Dementia Complex; Accounting; Antiviral Agents; Biochemical Genetics; Biology; CD4 Positive T Lymphocytes; Cell Communication; Cell Lineage; Cell Shape; Cells; Central Nervous System Infections; Characteristics; Chronic; Colony-Stimulating Factor Receptors; Cytokine Signaling; Disease Progression; Drug Delivery Systems; Exhibits; Goals; Growth; HIV; HIV Infections; HIV-1; Infection; Invaded; Laboratories; Lentivirus Infections; Longevity; Lymphocyte; Macaca; Mammalian Cell; Mediating; Microglia; Modeling; Myelogenous; Myeloid Cells; Nature; Neuraxis; Neurons; Pathogenicity; Phase; Phenotype; Play; Primate Lentiviruses; Primates; Production; Proteins; Proteomics; Research; Role; SIV; Shapes; Signal Transduction; TRIM Gene; Variant; Viral; Viral Cytopathogenic Effect; Virus; Virus Diseases; Virus Replication; Work; antiretroviral therapy; base; cytokine; defined contribution; in vivo; information gathering; interest; macrophage; monocyte; monocyte colony stimulating factor; mutant; novel; prevent; research study

DESCRIPTION (provided by applicant): Myeloid lineage cells (macrophage/microglia) are central to the ability of primate lentiviruses (HIV/SIV) to establish a viral reservoir in the central nervous system (CNS) and the presence of such a reservoir underscores the neuropathogenic manifestations of virus infection. However, beyond their role in CNS infection, it is not known whether monocyte/macrophage are even necessary for infection of the host by HIV/SIV and definitive experiments demonstrating such an essential role are lacking. Our studies on HIV- myeloid cell interaction have revealed the existence of viral determinants that specifically operate in monocyte/macrophage. These determinants are essential for the ability of the virus to invade the cell and for the ability of the virus to maintain a persistent infection. Based on this, we hypothesize that myeloid cells are essential for infection of the host and propose that strategies that truncate myeloid cell infection will fundamentally impact the course of infection by curtailing viral persistence, neuroinvasion and pathogenicity. To pursue this hypothesis, we propose the following specific aims: Aim 1: Examine the in vivo phenotype (replication, persistence, neuroinvasion) of SIV mutants incapable of infecting myeloid lineage cells. Our research has defined a viral determinant (Vpr/Vpx) that is essential for the infection of myeloid cells by HIV/SIV yet that is dispensable for infection of CD4+ T lymphocytes. Infection of macaques with these mutants will allow us to define how the myeloid cell reservoir shapes the course of viral replication, persistence and pathogenicity in vivo. Aim 2: Evaluate the contribution of myeloid reservoirs to chronic virus infection through the use of pharmacologic agents that truncate infected macrophage survival. Our research has established a mechanism by which monocyte/macrophage resist viral cytopathic effects that relies on the production and signaling of the survival cytokine monocyte colony stimulating factor (MCSF) by infected macrophage. We have determined that agents that interfere with the function of the MCSF receptor restore the sensitivity of macrophage to virus-mediated cytopathicity. We will examine whether pharmacologic inhibition of survival cytokine signaling curtails viral persistence in the macrophage phase of SHIVDH12 infection in macaques. Aim 3: Define the cellular factors that regulate myeloid cell infection by primate lentiviruses. Antiviral restrictions such as Apobec 3G and Tetherin have generated intense interest in the field. Our research reveals the existence of a novel antiviral factor that is specifically expressed by myeloid cells. This restriction potently inhibits myeloid cell infection by HIV/SIV and the viral Vpr/Vpx proteins counteract the antiviral activity of this restriction. We will use biochemical and genetic approaches to characterize the cellular activity that regulates myeloid cell infection. Studies outlined in this proposal will define the role of the myeloid cell reservoir in the biology of primate lentiviruses and in the interaction of primate lentiviruses with their hosts. This information will be used to devise strategies with which to prevent the establishment of HIV-1 infection in the host as well as strategies to curtail the chronic nature of virus infection. PUBLIC HEALTH RELEVANCE: Research over the past several years has highlighted that mammalian cells are not passive to infection by primate lentiviruses such as HIV-1. Rather, some proteins within mammalian cells potently antagonize the replication of primate lentiviruses. As a consequence, primate lentiviruses have evolved counter defenses in order to circumvent these "cellular restrictions". We have evidence for the existence of a novel cellular restriction that is specifically expressed by myeloid lineage cells such as macrophages. In this project we propose to identify the nature of the cellular restriction, the mechanism by which it antagonizes primate lentivirus replication and the role it plays in the establishment of myeloid cell reservoirs in vivo. Information gathered from this study will reveal new drug targets with which to prevent the establishment of myeloid cell reservoirs by primate lentiviruses thereby truncating the ability of these viruses to persist within the host. )

描述（由申请人提供）：髓样谱系细胞（巨噬细胞/小胶质细胞）对于灵长类动物（HIV/SIV）在中枢神经系统（CNS）中建立病毒储量的能力至关重要，并且存在这种储层的存在强调了病毒素感染的神经病变表现。但是，除了它们在中枢神经系统感染中的作用之外，尚不清楚单核细胞/巨噬细胞是否需要HIV/SIV感染宿主，并且缺乏证明这种重要作用的确定实验。我们对HIV-髓样细胞相互作用的研究表明，在单核细胞/巨噬细胞中专门起作用的病毒决定因素。这些决定因素对于病毒入侵细胞和病毒保持持续感染的能力至关重要。基于此，我们假设髓样细胞对于宿主感染至关重要，并提出截断髓样细胞感染的策略将通过减少病毒持久性，神经侵袭和致病性来从根本上影响感染的过程。为了提出这一假设，我们提出了以下特定目的：目标1：检查体内表型（复制，持久性，神经侵袭）的SIV突变体无法感染髓样谱系细胞。我们的研究定义了一种病毒决定因素（VPR/VPX），这对于通过HIV/SIV感染髓样细胞至关重要，但对于CD4+ T淋巴细胞的感染是可分配的。这些突变体的猕猴感染将使我们能够定义髓样细胞储层如何塑造体内病毒复制，持久性和致病性的过程。 AIM 2：通过使用截断感染巨噬细胞存活的药理剂，评估髓样库对慢性病毒感染的贡献。我们的研究已经建立了一种机制，单核细胞/巨噬细胞抵抗病毒细胞病毒作用，依赖于通过感染的巨噬细胞的生存细胞因子单核细胞刺激因子（MCSF）的生产和信号传导。我们已经确定，干扰MCSF受体功能的药物恢复了巨噬细胞对病毒介导的细胞病变的敏感性。我们将检查猕猴Shivdh12感染的巨噬细胞阶段中对生存细胞因子信号传导的药理抑制是否会减少病毒持久性。目标3：定义通过灵长类动病毒调节髓样细胞感染的细胞因子。抗病毒限制（例如Apobec 3G和Tetherin）对该领域产生了强烈的兴趣。我们的研究揭示了由髓样细胞特别表达的新型抗病毒因子的存在。这种限制可有效抑制HIV/SIV和病毒VPR/VPX蛋白抵消该限制的抗病毒活性。我们将使用生化和遗传方法来表征调节髓样细胞感染的细胞活性。该提案中概述的研究将定义髓样细胞储存库在灵长类动病毒生物学以及灵长类动病毒与宿主的相互作用中的作用。这些信息将用于制定策略，以防止在宿主中建立HIV-1感染以及减少病毒感染的慢性性质的策略。 公共卫生相关性：在过去的几年中，研究表明，哺乳动物细胞并不是灵长类动病毒（例如HIV-1）被动感染的。相反，哺乳动物细胞中的某些蛋白质有效地拮抗了灵长类动病毒的复制。结果，灵长类动物病毒已经进化出来的反防御，以规避这些“细胞限制”。我们有证据表明存在一种新型细胞限制，该细胞限制是由髓样谱系细胞（例如巨噬细胞）特别表达的。在这个项目中，我们建议识别细胞限制的性质，它拮抗灵长类动物慢病毒复制的机制及其在体内建立髓样细胞储量中所扮演的作用。从这项研究中收集的信息将揭示新的药物靶标，以防止灵长类动病毒通过灵长类动物建立髓样细胞储存剂，从而截断这些病毒在宿主内持续存在的能力。 ）