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（由申请人提供）：本R 01申请的主要目的是确定早期肠道粘膜感知和对HIV感染的反应，该HIV感染诱导肠道炎症并支持初始病毒传播并建立病毒储库。胃肠道粘膜是HIV感染的早期靶点，是严重的CD 4 + T细胞耗竭和肠道上皮屏障功能障碍的部位，导致免疫功能障碍和持续的免疫激活。虽然对慢性HIV感染的发病机制了解很多，但我们对肠道粘膜中最初的宿主-病毒相互作用及其对病毒传播、抗病毒粘膜免疫和粘膜对其他病原体和肠道微生物群的反应的潜在影响的了解有限。拟议研究的总体目标是通过以下方式研究肠道粘膜部位的早期宿主-病毒相互作用：（a）鉴定 负责对病毒的早期感知和应答的粘膜细胞和分子信号传导，以及它们在诱导肠道炎症和随后的病毒传播中的作用，和（B）通过实验干预这些早期宿主-病毒相互作用的功能作图。利用艾滋病的猴免疫缺陷病毒（SIV）模型，我们最近确定了以前未被认识到的潘氏细胞在早期粘膜感知和对病毒的反应中的作用，并可能引发肠道炎症。在SIV感染2.5天时，潘氏细胞中IL-1β表达的显著诱导引起上皮屏障结构完整性的变化。该提议的中心假设是潘氏细胞对病毒感染的细胞的感测和响应最初诱导IL-1β信号传导，并且可能通过肠上皮细胞破坏和粘膜T细胞循环驱动早期肠道炎症，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库。实验计划是基于我们在SIV模型、肠道粘膜免疫学和早期肠道粘膜对SIV感染细胞应答的初步数据方面的专业知识。拟议项目的目标将通过两个具体目标实现。目的1：研究潘氏细胞感知和早期病毒库建立的影响。肠道免疫和上皮细胞隔室对病毒感染的早期免疫应答的影响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 抗逆转录病毒治疗（ART）和IL-1β阻断在抑制潘氏细胞介导的肠道炎症β网络和预防/减少病毒传播中的作用。拟定的研究与早期粘膜感知和反应网络的识别和表征高度相关，这些网络可能驱动肠道炎症并支持病毒向粘膜免疫靶点的指数传播，并与理解通过ART和IL-1β抑制剂干预这些事件的影响高度相关。破译病毒感染早期传播的机制将提供新的治疗干预靶点，从而预防或限制早期病毒储库的建立。