Hepatitis C Virus Brain Infection in HCV/HIV Coinfection

描述(申请人提供)：越来越多的证据表明，感染丙型肝炎病毒(丙型肝炎病毒)与认知功能障碍有关，而认知功能障碍与肝脏损伤的程度无关。在HIV患者中，还记录了丙型肝炎病毒混合感染对神经认知的明显影响。丙型肝炎病毒被认为是严格的嗜肝细胞，但越来越多的证据表明，它也可以在外周血单核细胞中复制，包括单核/巨噬细胞，特别是在艾滋病毒感染的患者中。我们最近在感染患者的尸检脑组织中发现了包括病毒复制形式在内的丙型肝炎病毒RNA序列，这表明丙型肝炎病毒感染可能有直接的局部影响。 我们推测，丙型肝炎病毒的肝外复制与神经认知功能障碍直接相关，因为白细胞可以携带病毒穿过血脑屏障，感染中枢神经系统内的细胞。最有可能的目标细胞是脑巨噬细胞和小胶质细胞。目前的建议旨在描述与相关细胞有关的丙型肝炎病毒神经侵袭的特征以及对基因表达模式的可能影响。 具体来说，我们会： 1.采用激光捕获显微镜(LCM)和免疫组织化学染色技术，对HIV/HCV混合感染者尸检脑组织中的丙型肝炎病毒感染细胞类型进行鉴定。 2.应用基因芯片技术对丙型肝炎病毒感染者尸检脑组织、分离的脑巨噬细胞/小胶质细胞和神经细胞的基因表达谱进行分析。 这项拟议的研究将有助于阐明丙型肝炎病毒感染患者，特别是丙型肝炎病毒/艾滋病毒混合感染患者神经认知功能障碍的生物学基础。

DESCRIPTION (provided by applicant): There is growing evidence that infection with hepatitis C virus (HCV) is associated with cognitive dysfunction, which is unrelated to the degree of liver injury. Distinct neurocognitive effects of HCV coinfection were also documented in HIV patients. HCV was thought to be strictly hepatotropic, but there is mounting evidence that it can also replicate in peripheral blood mononuclear cells, including monocytes/macrophages, particularly in HIV-infected patients. We have recently found HCV RNA sequences, including viral replicative forms, in autopsy brain tissue from infected patients, which suggests the possibility of direct local effects of HCV infection. We postulate that extrahepatic replication of HCV is directly related to neurocognitive dysfunction as leukocytes could carry the virus across the blood-brain barrier and infect cells within the central nervous system. The most likely target cells are brain macrophages and microglia. The current proposal is aimed at characterizing HCV neuroinvasion with respect to involved cells and possible effects on gene expression patterns. Specifically, we will: 1. Determine the type of cells infected by HCV in autopsy brain tissue from HIV/HCV coinfected patients using laser capture microscopy (LCM) and immunostaining. 2. Characterize by microarray the gene expression pattern in autopsy brain tissue and in isolated brain macrophage/microglia and neuron cells from HCV-infected patients as compared to uninfected control patients. The proposed study will allow to clarify the biological basis of neurcognitive dysfunction encountered in HCV infected, and particularly in HCV/HIV coinfected patients.