HIV-Induced Immune Activation in Humanized MIce

描述（由申请人提供）：持续的免疫激活是HIV感染疾病进展的一个强有力的预测因子，其特征是所有免疫细胞类型的激活，促炎细胞因子水平的增加和激活诱导的淋巴细胞凋亡。近年来，微生物toll样受体（TLR）配体从肠道到体循环的易位已被认为是诱导免疫激活的一个主要因素。由此导致的炎症细胞因子的增加可能是免疫激活的根本原因和疾病进展的决定因素。在HIV感染中，与体循环微生物产物相关的细胞因子风暴、免疫激活和淋巴细胞凋亡也是自然和实验败血症的特征。巨噬细胞和树突状细胞分泌的HMGB1是脓毒症中细胞因子风暴的主要调节因子。我们最近的研究表明，通过靶向递送siRNA（通过一种名为RVG-9R的肽），在人源化BLT小鼠体内的人巨噬细胞和树突状细胞中沉默HMGB1，可以显著抑制败血症诱导的细胞因子风暴和死亡率。虽然HMGB1及下游细胞因子水平在HIV感染者中也升高，但其在慢性免疫激活中的作用尚不清楚。在本研究中，我们将利用人源化的HIV感染小鼠模型，测试HMGB1和下游细胞因子的作用、它们与微生物产物的关系以及抑制这些炎症介质对体内免疫激活和疾病进展的影响。在Aim 1中，我们将描述HIV感染的人源化小鼠在没有抗逆转录病毒治疗或接受抗逆转录病毒治疗的情况下的全谱免疫激活。在第二个目标中，我们将测试通过靶向递送siRNA到巨噬细胞和树突状细胞来沉默HMGB1或下游细胞因子是否可以减少感染小鼠的免疫激活和疾病进展。

DESCRIPTION (provided by applicant): Persistent immune activation is a strong predictor of disease progression in HIV infection and is characterized by activation of all immune cell types, increased levels of proinflammatory cytokines and activation-induced lymphocyte apoptosis. Translocation of microbial toll-like receptor (TLR) ligands from the gut to the systemic circulatio has been recognized in recent years to be a major factor in inducing immune activation. The resulting increase in inflammatory cytokines may be the fundamental cause for immune activation and determinant of disease progression. The cytokine storm, immune activation and lymphocyte apoptosis attended with microbial products in systemic circulation seen in HIV infection also characterizes natural and experimental sepsis. HMGB1 secreted from macrophages and dendritic cells acts as a master regulator of cytokine storm in sepsis. We have recently shown that silencing HMGB1 in human macrophages and dendritic cells in vivo in humanized BLT mice by targeted delivery of siRNA (via a peptide called RVG-9R) dramatically suppressed the sepsis-induced cytokine storm and mortality. Although serum level of HMGB1 as well as downstream cytokines are also elevated in HIV infected individuals, their role in chronic immune activation is not clear. In this proposal, we will test the role of HMGB1 and downstream cytokines, their relation to microbial products and the effect of suppressing these inflammatory mediators on immune activation and disease progression in vivo using the humanized mouse model for HIV infection. In Aim 1, we will characterize the full spectrum of immune activation in HIV infected humanized mice without or with ART. In the second aim we will test if silencing HMGB1 or downstream cytokines by targeted delivery of siRNA to macrophages and dendritic cells can reduce immune activation and disease progression in infected mice.