HCV Replication and Immune Response in HIV Coinfection

描述（由申请人提供）：大约20%的人类免疫缺陷病毒（HIV）阳性个体也感染丙型肝炎病毒（HCV）。最近的研究报告说，艾滋病毒加速丙型肝炎疾病的进程，可能是由于丙型肝炎病毒的免疫控制的损失。我们已经确定了两个与更严重的丙型肝炎疾病相关的病毒学变量：HCV准种（QS）的遗传变异性降低，以及感染肝脏内HCV复制指数增加。我们的初步研究表明，HCV免疫反应可能与这两个变量有关。我们在此提出了新的证据表明，HCV在自然感染期间在体内肝周淋巴结中的T淋巴细胞中有效复制，这表明了一种新的疾病机制。这项竞争性更新申请中提出的研究将扩大我们对有和没有HIV合并感染的受试者中慢性HCV感染的病毒学和免疫学的关注。目的1将解决HCV单感染和HCV/HIV共感染受试者的肝脏和PBMC内HCV QS变体的组织区室化。我们预测HIV合并感染将导致外周血细胞中HCV复制的增加，并且PBMC限制性HCV QS将成为血清相关HCV QS的更主要成分。目的2将解决以下假设：1）肝内免疫应答与体内HCV复制下调相关; 2）宿主免疫应答驱动HCV QS多样化; 3）慢性HCV感染期间发生隔室特异性免疫。目的3研究HCV QS在体外细胞培养中的感染性。该目的将检验以下假设：与肝细胞类型相比，某些HCV QS在造血细胞中固有地复制更好（反之亦然），以及HIV合并感染促进HCV在血细胞类型中复制。拟议的研究将是第一个同时评估肝脏与外周血中的抗HCV免疫应答及其对肝内HCV复制和同一天从我们的研究受试者中收集的血清、肝脏和血液标本中的HCV QS变异性的影响的研究。该研究还将研究HIV合并感染对体内HCV-宿主生物学和体外组织培养中HCV-HIV相互作用的影响，有助于我们了解合并感染如何加速丙型肝炎疾病。

DESCRIPTION (provided by applicant): Approximately 20% of human immunodeficiency virus (HlV)-positive individuals are also infected with hepatitis C virus (HCV). Recent studies report that HIV accelerates hepatitis C disease course, perhaps due to loss of immune control of HCV. We have identified two virological variables associated with more severe hepatitis C disease: decreased genetic variability of HCV quasispecies (QS), and increased indices of HCV replication within infected livers. Our preliminary studies suggest that HCV immune responses may be related to both variables. We present herein new evidence that HCV productively replicates in T lymphocytes residing in peri-hepatic lymph nodes in vivo during natural infection, suggesting a novel mechanism of disease. The research proposed in this competitive renewal application will extend our focus on the virology and immunology of chronic HCV infection in subjects with and without HIV coinfection. Aim 1 will address tissue compartmentalization of HCV QS variants within liver and PBMCs of HCV-monoinfected and HCV/HIV coinfected subjects. We predict that HIV coinfection will lead to an increase in HCV replication in peripheral blood cells, and that PBMC-restricted HCV QS will become a more predominant constituent of serum-associated HCV QS. Aim 2 will address the following hypotheses: 1) intrahepatic immune responses are associated with down-regulation of HCV replication in vivo; 2) host immune responses drive HCV QS diversification, and 3) compartment-specific immunity occurs during chronic HCV infection. Aim 3 proposes to study the infectivity of HCV QS isolated from study subjects in cell culture in vitro. This Aim will test the hypotheses that certain HCV QS inherently replicate better in hematopoetic cells compared to hepatic cell types (and visa versa), and that HIV coinfection facilitates HCV replication in blood cell types. The proposed studies will be the first to simultaneously assess anti-HCV immune responses in liver versus peripheral blood and their effect on intrahepatic HCV replication and HCV QS variability in serum, liver and blood specimens collected from our research subjects on the same day. The study will also examine the effect of HIV coinfection on HCV-host biology in vivo and HCV-HIV interactions in tissue culture in vitro, contributing to our understanding of how coinfection accelerates hepatitis C disease.