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：
8519044
负责人：
Jarrod Sean Johnson
金额：
$ 0.31万
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 2013-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8519044
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) 感染会导致 CD4+ T 细胞的毁灭性损失并发展为获得性免疫缺陷综合征 (AIDS)。截至 2010 年，全世界大约有 3330 万人感染艾滋病毒/艾滋病 (44, 49)，尽管出现了抗逆转录病毒疗法，艾滋病毒感染仍然被认为是全球流行病。有效的艾滋病毒疫苗或治疗方法仍然难以捉摸，部分原因是免疫系统如何感知艾滋病毒的基本原理尚不完全清楚。如何减少艾滋病毒感染的线索可以在被称为“精英控制者”的艾滋病毒感染者群体中找到，他们能够将血浆病毒粒子水平维持在每毫升 50 拷贝以下，并且不会发展为艾滋病。这些罕见个体表现出卓越的“控制”病毒感染的能力，与其他感染个体相比，它们表现出性质不同的 CD8+ T 细胞反应，这对于宿主控制病毒血症可能至关重要。通过这个项目，我们试图阐明树突状细胞（DC）中 HIV 介导的免疫反应激活途径，树突状细胞是专业的抗原呈递细胞，将微生物的先天检测与细胞和适应性免疫反应联系起来。我们的实验室最近表明，DC 中存在干扰素调节因子 3 (IRF3) 依赖性的对 HIV 的先天反应 (24)，但这种反应是神秘的，因为 HIV 通常不会感染 DC。在这个项目中，我们将研究树突状细胞中先天免疫信号传导途径，并评估细胞成分如何“感知”病毒感染。为此，我们提出以下目标：1）探索HIV-1如何通过IRF3途径影响DC的先天反应； 2) 检查 DC 的先天激活和细胞因子产生是否与感染 HIV 的精英控制者有根本不同。最终，我们希望重述精英控制者中可能发挥作用的过程，并提高我们对艾滋病毒发病机制的理解。