Evaluating Innate Immune Responses in Dendritic Cells During HIV Infection

评估 HIV 感染期间树突状细胞的先天免疫反应

基本信息

批准号：
8330070
负责人：
Jarrod Sean Johnson
金额：
$ 5.22万
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：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330070
关键词：
Acquired Immunodeficiency Syndrome Affect Anti-Retroviral Agents Antigen-Presenting Cells Antigens Autologous Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Capsid Proteins Cells Collaborations Cyclosporine Cytokine Activation Dendritic Cells Detection Dimerization Disease Epidemic Exhibits Fostering Gagging Gene Expression HIV HIV-1 Immune Immune response Immune system Immunofluorescence Microscopy Individual Infection Institutes Interferon Type I Interferon Type II Interferons Laboratories Lead Libraries Life Light Link Maps Mediating Mind Molecular Profiling Pathway interactions Pharmaceutical Preparations Phosphorylation Plasma Play Population Process Production SIV Signal Transduction T cell response T-Cell Proliferation T-Lymphocyte Testing Vaccines Viral Viremia Virion Virus Virus Diseases Work base design enzyme linked immunospot assay human IRF3 protein immune activation improved insight interferon regulatory factor-3 microorganism monocyte mutant pandemic disease response small hairpin RNA vector virus pathogenesis

项目摘要

Infection with human immunodeficiency virus (HIV) leads to the devastating loss of CD4+ T cells and progression to acquired immunodeficiency syndrome (AIDS). As of 2010, roughly 33.3 million people were living with HIV/AIDS worldwide (44, 49), and despite the advent of anti-retroviral therapy, HIV infection is still considered a global pandemic. An effective vaccine or cure for HIV infection remains elusive in part because basic principles of how HIV is sensed by the immune system are not completely clear. Clues for how HIV infection could be curtailed can be found in a population of HIV-infected individuals termed 'elite controllers', that are able to maintain plasma levels of virions to less than 50 copis per ml and do not progress to AIDS. These rare individuals exhibit a remarkable ability to 'control' viral infection and compared to other infected individuals they display a qualitatively different CD8+ T cell response, which may be critical for host control of viremia. With this projec we seek to elucidate pathways of HIV-mediated activation of immune responses in dendritic cells (DCs), professional antigen presenting cells that link innate detection of microorganisms to cellular and adaptive immune responses. Our laboratory has recently shown the existence of an interferon regulatory factor 3 (IRF3)-dependent innate response to HIV in DCs (24), but this response is cryptic since HIV does not typically infect DCs. For this project we will study pathways of innate immune signaling in DCs and evaluate how cellular components can 'sense' viral infection. To this end we propose the following aims: 1) explore how HIV-1 influences an innate response in DCs through the IRF3 pathway; and 2) examine whether innate activation and cytokine production in DCs is fundamentally different in HIV-infected elite controllers. Ultimately, we hope to recapitulate what processes may be at play in elite controllers and improve our understanding of HIV pathogenesis.

人类免疫缺陷病毒（HIV）的感染导致CD4+ T细胞的毁灭性丧失，并发展为获得的免疫缺陷综合征（AIDS）。截至2010年，全球大约有3330万人患有艾滋病毒/艾滋病（44，49），尽管抗逆转录病毒疗法出现了，但艾滋病毒感染仍被认为是全球性大流行。一种有效的艾滋病毒感染疫苗或治疗仍然难以捉摸，部分原因是免疫系统如何感知HIV的基本原理并不完全清楚。在称为“精英控制者”的艾滋病毒感染者中，可以发现如何减少HIV感染的线索，这些人能够将血浆水平的病毒粒子水平维持在每毫升不足50 copis且不发展为艾滋病。这些罕见的个体具有“控制”病毒感染的显着能力，并将其与其他受感染的个体进行了比较，它们在质量上不同的CD8+ T细胞反应表现出了不同的能力，这对于病毒血症的宿主控制可能至关重要。使用此ProJEC，我们试图阐明树突状细胞中免疫反应激活的途径（DCS），专业抗原呈现细胞，这些细胞将微生物的先天检测与细胞和适应性免疫反应联系起来。我们的实验室最近显示了干扰素调节因子3（IRF3）对DC中对HIV的先天反应的存在（24），但是这种反应是隐秘的，因为HIV通常不感染DCS。对于这个项目，我们将研究DC中先天免疫传导的途径，并评估细胞成分如何“感知”病毒感染。为此，我们提出以下目的：1）探索HIV-1如何通过IRF3途径影响DC中的先天反应； 2）检查DC中的先天激活和细胞因子的产生在HIV感染的精英控制器中是否根本不同。最终，我们希望概括出精英控制器中可能在发挥哪些过程，并提高我们对HIV发病机理的理解。