Dendritic Cell Dynamics in Peripheral and Lymphoid Tissues in SIV Infection

描述（由申请人提供）：树突状细胞（DC）和单核细胞/巨噬细胞（Mo/M？）是先天性免疫细胞，B介导抗病毒活性和诱导适应性免疫应答，在宿主对病毒感染的应答中发挥关键作用。然而，在人类免疫缺陷病毒（HIV）感染的人类中，DC、Mo/M？和病毒控制之间的这种关系尚不清楚，因为作为进展为AIDS的中心特征的全身性免疫激活可能由对感染的过度活跃的先天免疫应答驱动。因此，在HIV发病机制中一个未回答的中心问题是DC和Mo/M？对感染的反应是可取的还是有害的。这是该领域进展的一个关键障碍，因为我们不知道治疗策略的目的是阻断还是促进先天免疫。在这个建议中，我们将解决这个中心问题，在猴免疫缺陷病毒（SIV）感染恒河猴，模型艾滋病毒感染的人类。我们将前瞻性研究DC和Mo/M <$反应在SIVmac 251感染的猕猴与控制感染与正常或快速进展，并比较这与SIVmac 251感染的猕猴和抗逆转录病毒治疗或感染减毒SIVmac 239 <$nef。有了这一感染结果的全谱，我们将能够将DC和Mo/M？反应与AIDS发病机制的相关性置于背景中。此外，我们将使用一种对DC的一个子集（浆细胞样DC）具有特异性的新型人源化抗体，在感染时或慢性期耗尽这些细胞。这将首次使我们能够直接确定浆细胞样DC对病毒控制和慢性免疫激活的贡献。这些假设驱动的研究将进一步确定DC和Mo/M？在HIV感染中的作用，并为开发针对先天免疫的治疗方法提供方向。

DESCRIPTION (provided by applicant): Dendritic cells (DC) and monocytes/macrophages (Mo/M¿) are innate immune cells that play a critical role in the host response to viral infection b mediating antiviral activity and inducing adaptive immune responses. However, in human immunodeficiency virus (HIV) infection of humans this relationship between DC, Mo/M¿ and virus control is not clear, as generalized immune activation that is a central feature of progression to AIDS may be driven by an overactive innate immune response to infection. Hence, a central unanswered question in HIV pathogenesis is whether the DC and Mo/M¿ response to infection is desirable or detrimental. This represents a critical impediment to progress in the field, as we do not know if therapeutic strategies should be aimed at blocking or promoting innate immunity. In this proposal we will address this central question in simian immunodeficiency virus (SIV) infection of rhesus macaques, which models HIV infection of humans. We will prospectively study the DC and Mo/M¿ response in SIVmac251-infected macaques with controlled infection vs. normal or rapid progression and compare this to macaques infected with SIVmac251 and treated with antiretroviral therapy or infected with attenuated SIVmac239¿nef. With this full spectrum of outcomes of infection we will be able to put into context the relevance of the DC and Mo/M¿ response to AIDS pathogenesis. In addition, we will use a novel humanized antibody specific for one subset of DC, the plasmacytoid DC, to deplete these cells at the time of infection or during the chronic phase. This will, for the first time, allow us to directly determine the contribution of plasmacytoid DC to virs control and chronic immune activation. These hypothesis-driven studies will further define the role of DC and Mo/M¿ in HIV infection and provide direction for development of therapeutics targeting innate immunity.