Evaluating Innate Immune Responses in Dendritic Cells During HIV Infection

感染人类免疫缺陷病毒(HIV)会导致CD4+T细胞的毁灭性丧失，并进展为获得性免疫缺陷综合征(AIDS)。截至2010年，全世界约有3330万艾滋病毒/艾滋病患者(4449人)，尽管出现了抗逆转录病毒疗法，但艾滋病毒感染仍被认为是一种全球流行病。艾滋病毒感染的有效疫苗或治愈方法仍然难以捉摸，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。关于如何减少艾滋病毒感染的线索可以在一群艾滋病毒感染者身上找到，这些人被称为“精英控制者”，他们能够将血浆中的病毒粒子水平维持在每毫升低于50 Copis，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，与其他感染个体相比，他们表现出本质上不同的CD8+T细胞反应，这可能是宿主控制病毒血症的关键。通过这个项目，我们试图阐明HIV介导的树突状细胞(DC)免疫反应激活的途径，树突状细胞是将微生物的先天检测与细胞和适应性免疫反应联系起来的专业抗原提呈细胞。我们的实验室最近发现在DC中存在依赖干扰素调节因子3(IRF3)的先天对HIV的反应(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的途径，并评估细胞成分如何“感觉”病毒感染。为此，我们提出了以下目标：1)探索HIV-1如何通过IRF3途径影响DC的先天反应；2)检查感染HIV的精英控制者DC的先天激活和细胞因子产生是否有根本不同。最终，我们希望总结精英控制者可能发挥的作用过程，并提高我们对艾滋病毒发病机制的理解。

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.