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。HCV合并感染在HIV患者中也有明显的神经认知影响。HCV被认为是严格意义上的嗜肝性病毒，但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/巨噬细胞）中复制，特别是在hiv感染患者中。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感染可能直接局部影响。

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.