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

• 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
• 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

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）感染导致CD 4 + T细胞的毁灭性损失并进展为获得性免疫缺陷综合征（AIDS）。截至2010年，全世界约有3330万人感染艾滋病毒/艾滋病（44，49），尽管抗逆转录病毒疗法的出现，艾滋病毒感染仍然被认为是一种全球流行病。一种有效的疫苗或治疗艾滋病毒感染的方法仍然难以捉摸，部分原因是免疫系统如何感知艾滋病毒的基本原理还不完全清楚。如何减少艾滋病毒感染的线索可以在被称为“精英制造商”的艾滋病毒感染者群体中找到，这些人能够将病毒粒子的血浆水平维持在每毫升50 copis以下，并且不会发展为艾滋病。这些罕见的个体表现出显著的“控制”病毒感染的能力，并且与其他感染个体相比，它们表现出性质上不同的CD 8 + T细胞应答，这可能对宿主控制病毒血症至关重要。通过这个项目，我们试图阐明树突状细胞（DC）中HIV介导的免疫应答激活的途径，树突状细胞是将微生物的先天检测与细胞和适应性免疫应答联系起来的专业抗原呈递细胞。我们的实验室最近显示了在DC中存在干扰素调节因子3（IRF 3）依赖性的对HIV的先天性应答（24），但是这种应答是神秘的，因为HIV通常不感染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的途径，并评估细胞成分如何“感知”病毒感染。为此，我们提出了以下目标：1）探索HIV-1如何通过IRF 3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产生是否在HIV感染的精英控制者中有根本性的不同。最终，我们希望概括哪些过程可能在精英控制者中起作用，并提高我们对HIV发病机制的理解。