Dendritic Cell Dynamics in Peripheral and Lymphoid Tissues in SIV Infection

描述(申请人提供)：树突状细胞(DC)和单核/巨噬细胞(Mo/M)是先天免疫细胞，在宿主对病毒感染的反应中发挥关键作用，介导抗病毒活性和诱导适应性免疫反应。然而，在人类免疫缺陷病毒(HIV)感染中，DC、Mo/M和病毒控制之间的这种关系尚不清楚，因为作为进展为艾滋病的中心特征的全身性免疫激活可能是由对感染的过度活跃的先天免疫反应驱动的。因此，HIV发病机制中的一个中心悬而未决的问题是，DC和Mo/M对感染的反应是可取的还是有害的。这是在这一领域取得进展的一个严重障碍，因为我们不知道治疗战略应该是以阻止还是促进先天免疫为目标。在这项提案中，我们将解决猴免疫缺陷病毒(SIV)感染恒河猴这一核心问题，它是人类感染HIV的模型。我们将前瞻性地研究感染SIVmac251的猕猴与正常或快速进展的SIVmac251感染的猕猴的DC和Mo/M？反应，并将其与感染SIVmac251并接受抗逆转录病毒治疗的猕猴或感染减毒SIVmac239？nef的猕猴进行比较。有了感染的全部结果，我们将能够了解DC和Mo/M反应与艾滋病发病机制的相关性。此外，我们将使用一种新的针对DC亚群的人源化抗体，即浆细胞样树突状细胞，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血浆细胞样树突状细胞在VIRS控制和慢性免疫激活中的作用。这些假说驱动的研究将进一步确定DC和Mo/M在HIV感染中的作用，并为针对天然免疫的治疗药物的发展提供方向。

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.