Hepatitis C Virus Brain Infection in HCV/HIV Coinfection

描述（由申请人提供）：越来越多的证据表明，丙型肝炎病毒（HCV）感染与认知功能障碍有关，而认知功能障碍与肝损伤程度无关。在HIV患者中也记录了HCV合并感染对神经认知的明显影响。HCV被认为是严格嗜肝的，但有越来越多的证据表明，它也可以在外周血单核细胞，包括单核细胞/巨噬细胞，特别是在HIV感染的患者中复制。我们最近在感染患者的尸检脑组织中发现了HCV RNA序列，包括病毒复制形式，这表明HCV感染的直接局部效应的可能性。 我们推测HCV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并感染中枢神经系统内的细胞。最可能的靶细胞是脑巨噬细胞和小胶质细胞。目前的建议是旨在表征HCV神经侵袭有关的细胞和基因表达模式的可能影响。 具体而言，我们将： 1.采用激光捕获显微镜（LCM）和免疫染色法确定HIV/HCV合并感染患者尸检脑组织中HCV感染细胞的类型。 2.通过微阵列表征与未感染的对照患者相比，HCV感染患者尸检脑组织和分离的脑巨噬细胞/小胶质细胞和神经元细胞中的基因表达模式。 这项研究将有助于阐明HCV感染者，特别是HCV/HIV合并感染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.