HIV Dysregulation of Human Plasmacytoid Dendritic Cells

HIV对人类浆细胞样树突状细胞的失调

基本信息

批准号：
8444570
负责人：
Meagan P O'Brien
金额：
$ 1.86万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444570
关键词：
Acquired Immunodeficiency Syndrome Acute Affect Agonist Anti-Retroviral Agents Antigen Presentation Antigen-Presenting Cells Antiviral Agents Basic Science Blood donor CD4 Positive T Lymphocytes Cell Communication Cells Cellular biology Chronic Clinical Communicable Diseases Dendritic Cells Development Disease Early Endosome Endocytosis Experimental Designs Feedback Fellowship Functional disorder Glycoproteins Goals HIV HIV Infections HIV vaccine Health Herpes Simplex Infections Human Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunology In Vitro Individual Infection Inflammation Inflammatory Influenza Interferon-alpha Interferons Intervention K-Series Research Career Programs Laboratories Life Link Mentors Myelogenous Natural Immunity Pathogenesis Pathway interactions Pattern Peer Review Pharmaceutical Preparations Phenotype Preventive Production Property Publications Qualifying Recruitment Activity Refractory Research Design Research Personnel Research Project Grants SIV Scientist Sendai virus Signal Pathway Signal Transduction TLR7 gene TLR9 gene Testing Toll-like receptors Training Translational Research Virion Virus Vulnerable Populations adaptive immunity career cell type chemokine cytokine immune activation improved in vivo response skills therapeutic vaccine trafficking transmission process virology

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal for a Mentored Clinical Scientist Career Development Award is for the candidate to achieve expertise in immunology and study design so that she may become an independent investigator in Human Immunodeficiency-1 (HIV) translational research. The candidate's expertise in clinical Infectious Diseases and ongoing immunology basic science training makes her highly qualified for the Career Development Award. Dr. Nina Bhardwaj, the candidate's mentor for this application, is expert in dendritic cell biology and has authored more than 130 peer-reviewed publications and has mentored more than 35 trainees, including 4 recipients of the K award. Since being recruited to the Bhardwaj laboratory during her fellowship in Infectious Diseases, the candidate has already made important contributions to the field of HIV immunology. The candidate's career plan focuses on enhancing skills in immunology, virology, and experimental design to become an independent researcher. The candidate's proposed research project centers on the idea that HIV dysregulates plasmacytoid dendritic cells (pDC) to activate deficient adaptive immune responses while stimulating persistent interferon-alpha (IFNa) production, thought to contribute to pathogenic inflammation and chronic immune activation, the driver of AIDS. pDCs are antigen presenting cells that are specialized to produce IFNa and to activate adaptive immune responses. Although IFNa inhibits HIV replication in vitro, the production of IFNa by HIV-activated pDCs in vivo likely contributes more to HIV pathogenesis than to protection. The candidate has shown that pDCs isolated from acutely HIV-infected subjects produce markedly elevated IFNa upon stimulation with HIV, as compared to pDCs from healthy subjects, contributing to the "cytokine storm" of acute HIV. Moreover, the candidate has shown that HIV activates abnormally persistent IFNa production by pDCs. She has shown that endocytosed HIV virions are retained in pDC cellular compartments that activate IFNa signaling pathways instead of trafficking to pDC cellular compartments that activate pathways necessary for maturation, antigen-presentation, and negative feedback of IFNa signaling pathways. In this application the candidate proposes to 1) study whether pDCs from chronically HIV-infected subjects produce elevated IFN in response to HIV stimulation, whether the degree of excess IFN correlates with immune activation, and whether pDCs from HIV- infected subjects may be modulated to inhibit persistent IFN responses and to improve adaptive immune responses, and 2) discover why HIV is retained in early endosomes to stimulate persistent IFN production and to determine how this trafficking pattern may be manipulated to inhibit persistent IFN and to enhance antigen-presentation

描述（由申请人提供）：这项指导的临床科学家职业发展奖的这一建议的目的是为了获得免疫学和研究设计方面的专业知识，以便她成为人类免疫缺陷-1（HIV）转化研究的独立研究者。候选人在临床传染病和持续的免疫学基础科学培训方面的专业知识使她获得了职业发展奖。该应用程序候选人的导师Nina Bhardwaj博士是树突细胞生物学的专家，已撰写了130多家经过同行评审的出版物，并指导了35名以上的学员，其中包括4名K奖获得者。自从在传染病研究金研究金期间被招募到Bhardwaj实验室以来，候选人已经为HIV免疫学领域做出了重要贡献。候选人的职业计划着重于增强免疫学，病毒学和实验设计的技能，成为一名独立研究人员。候选人提出的研究项目集中在HIV失调的想法中，质子型树突状细胞（PDC）激活缺乏的适应性免疫反应，同时刺激持续的干扰素-α（IFNA）产生，从而有助于致病性炎症和慢性免疫激活，这是AIDS的驾驶员。 PDC是抗原呈现的细胞，专门用于产生IFNA并激活适应性免疫反应。尽管IFNA在体外抑制了HIV复制，但由HIV激活的PDC在体内产生IFNA可能对HIV发病机理的贡献更大，而不是对保护。候选人表明，与健康受试者的PDC相比，从急性HIV感染受试者中分离出的PDC会产生显着升高的IFNA，这导致了急性HIV的“细胞因子风暴”。此外，候选人表明，HIV激活了PDC的异常持久性IFNA产生。她表明，内吞HIV病毒体保留在PDC细胞室中，这些室内激活IFNA信号传导途径，而不是运输到PDC细胞隔室，这些PDC细胞室激活了成熟，抗原预感所必需的途径以及IFNA信号通路的负反馈。 In this application the candidate proposes to 1) study whether pDCs from chronically HIV-infected subjects produce elevated IFN in response to HIV stimulation, whether the degree of excess IFN correlates with immune activation, and whether pDCs from HIV- infected subjects may be modulated to inhibit persistent IFN responses and to improve adaptive immune responses, and 2) discover why HIV is retained in early endosomes to stimulate持续的IFN产生并确定如何操纵这种运输模式以抑制持续的IFN并增强抗原表现