Early HIV Effects on Gut Immunity and Inflammation for Seeding Viral Reservoirs

早期艾滋病毒对肠道免疫和炎症的影响，以播种病毒库

• 批准号: 9154447
• 负责人: Satya Dandekar
• 金额: $ 77.84万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9154447
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antiviral Agents; CD4 Positive T Lymphocytes; Cell Cycle; Cells; Chronic; Communicable Diseases; Data; Dissection; Electron Microscopy; Epithelial; Epithelial Cells; Evaluation; Event; Experimental Designs; Functional disorder; Gene Expression; Genomics; Goals; HIV; HIV Infections; Immune; Immune System Diseases; Immune Targeting; Immune response; Immunity; Immunohistochemistry; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory disease of the intestine; Interferons; Interleukin-1 beta; Intervention; Intestines; Intravenous; Knowledge; Lasers; Lead; Macaca mulatta; Maps; Mediating; Modeling; Molecular; Molecular Profiling; Mucosal Immunity; Mucous Membrane; Outcome; Outcome Study; Paneth Cells; Pathogenesis; Pathologic; Patients; Production; Ramp; Recovery; Research; Role; SIV; Seeds; Signal Pathway; Signal Transduction; Site; Staging; Structure; T-Cell Depletion; T-Lymphocyte; Therapeutic Intervention; Tissues; Vaccines; Viral; Viral Load result; Viral Pathogenesis; Viral Proteins; Viral reservoir; Virus; Virus Diseases; anakinra; base; chemokine; cytokine; electron tomography; gastrointestinal; immune activation; in vivo; inhibitor/antagonist; microbiota; mucosal site; nonhuman primate; novel; pathogen; peripheral blood; pinacolyl methylphosphonic acid; prevent; programs; public health relevance; receptor; research study; response; restoration; therapy development; virus host interaction

 DESCRIPTION (provided by applicant): The main objective of this R01 application is to determine the early gut mucosal sensing and response to HIV infection that induces gut inflammation and support initial viral dissemination and establishes viral reservoirs. Gastrointestinal mucosa is an early target of HIV infection and a site of severe CD4+ T cell depletion and gut epithelial barrier dysfunction, which leads to immune dysfunction and persistent immune activation. While much is known about the pathogenesis of chronic HIV infection, our knowledge is limited about the initial host- virus interactions in the gut mucosa an their potential impact on the viral dissemination, anti-viral mucosal immunity and mucosal response to other pathogens and commensal microbiota. The overall goal of the proposed research is to investigate early host-virus interactions at the gut mucosal site by (a) identifying mucosal cells and molecular signaling responsible for early sensing and response to the virus and their role in the induction of gut inflammation and subsequent viral dissemination and (b) functional mapping through experimentally intervening these early host-viral interactions. Using the simian immunodeficiency virus (SIV) model of AIDS, we recently identified previously unrecognized role of Paneth cells in early mucosal sensing and response to the virus and for potentially initiating the gut inflammation. Marked induction of IL-1β expression in Paneth cells at 2.5 days of SIV infection caused changes in the epithelial barrier structural integrity. The central hypothesis of this proposal is that Paneth cell sensing and response to virus-infected cells initially induces IL-1β signaling, and may drive early gut inflammation through gut epithelil disruption and mucosal T cell cycling that in turn will support exponential increase in viral dissemination and establish stable viral reservoirs. The experimental plans are based on our expertise in the SIV model, gut mucosal immunology and preliminary data on early gut mucosal responders to SIV infected cells. The goals of the proposed project will be achieved through two specific aims. Aim 1: To investigate the impact of Paneth cell sensing and establishment of early viral reservoirs. The effects of early immune responses to viral infection by gut immune and epithelial cell compartments and their contribution to further viral dissemination will be investigated through in vivo and in vitro intestinal analyses. Aim 2: Determine the impact of early anti- retroviral therapy (ART) and of IL-1β blockade in dampening Paneth cell mediated gut inflammation β network and preventing/ reducing the viral dissemination. The proposed studies are highly relevant to the identification and characterization of early mucosal sensing and response networks that may drive gut inflammation and support an exponential spread of virus to mucosal immune targets and to understanding of the impact of intervening these events through ART and IL-1β inhibitor. Deciphering the mechanisms of the early spread of viral infection will provide novel targets of therapeutic intervention that will prevent or limit the establishment of early viral reservoirs.

 描述（由应用程序提供）：R01应用的主要目的是确定早期的肠粘膜感应和对HIV感染的反应，从而诱导肠道注射并支持初始病毒传播并建立病毒储量。胃肠道粘膜是HIV感染的早期靶标，是​​严重的CD4+ T细胞部署和肠上皮屏障功能障碍的部位，可导致免疫功能障碍和持久性免疫激活。尽管对慢性艾滋病毒感染的发病机理知之甚少，但我们的知识仅限于肠道粘膜中最初的宿主病毒相互作用，其对病毒传播，抗病毒粘膜免疫学和对其他病原体和共生微生物群的粘膜反应的潜在影响。拟议研究的总体目标是通过（a）识别肠粘膜部位的早期宿主病毒相互作用 粘膜细胞和分子信号传导负责早期敏感性和对病毒的反应及其在肠道注射诱导和随后的病毒传播中的作用，以及（b）通过实验性地介入这些早期宿主 - 病毒相互作用的功能映射。使用艾滋病的猿猴免疫缺陷病毒（SIV）模型，我们最近确定了潘埃斯细胞在早期粘膜敏感性和对病毒的反应中的先前未识别的作用，并可能引发肠道炎症。在SIV感染的2.5天内，在Paneth细胞中显着诱导IL-1β表达会导致上皮屏障结构完整性的变化。该提案的中心假设是，泛池细胞感应和对感染病毒的细胞的反应最初会诱导IL-1β信号传导，并且可能通过肠道上皮上皮破坏和粘膜T细胞循环促进早期肠道注射，这反过来将支持病毒传播的指数增加并建立稳定的病毒储量。实验计划基于我们在SIV模型，肠粘膜免疫学和早期肠粘膜反应者对SIV感染细胞的初步数据的基础。拟议项目的目标将通过两个具体目标来实现。目的1：研究Paneth细胞感测和建立早期病毒储存的影响。肠道免疫和上皮细胞室对病毒感染的早期免疫反应及其对进一步病毒传播的贡献将通过体内和体外肠道分析进行研究。目标2：确定早期的影响 在破坏Paneth细胞介导的肠道注射β网络并防止/减少病毒传播的抗逆转录病毒疗法（ART）和IL-1β阻断中。提出的研究与早期粘膜感应和反应网络的鉴定和表征高度相关，这些粘膜感应和反应网络可能会推动肠道注射并支持病毒到粘膜免疫靶标的指数扩散，并了解通过ART和IL-1β抑制剂介入这些事件的影响。解释病毒感染早期扩散的机制将提供热干预的新目标，以防止或限制早期病毒储备的建立。