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（HlV）阳性个体同时感染丙型肝炎病毒（HCV）。最近的研究报道，HIV加速了丙型肝炎的病程，可能是由于失去了对丙型肝炎病毒的免疫控制。我们已经确定了与更严重的丙型肝炎疾病相关的两个病毒学变量：HCV准种遗传变异（QS）的降低，以及感染肝脏内HCV复制指数的增加。我们的初步研究表明，HCV免疫反应可能与这两个变量有关。在此，我们提出了新的证据，表明HCV在自然感染期间在体内肝周围淋巴结的T淋巴细胞中有效复制，这提示了一种新的疾病机制。在这个竞争性更新申请中提出的研究将扩展我们对慢性HCV感染的病毒学和免疫学的关注，这些慢性HCV感染的受试者有和没有HIV合并感染。目的1将研究HCV-单感染和HCV/HIV合并感染受试者肝脏和PBMCs中HCV QS变异的组织区室化。我们预测HIV合并感染将导致HCV在外周血中的复制增加，并且pbmc限制性HCV QS将成为血清相关HCV QS的主要组成部分。目的2将探讨以下假设：1)肝内免疫反应与体内HCV复制的下调有关；2)宿主免疫反应驱动HCV QS多样化；3)慢性HCV感染发生室特异性免疫。目的3在体外细胞培养中研究从研究对象分离的HCV QS的传染性。本研究将验证以下假设：某些HCV QS在造血细胞中比在肝细胞类型中复制得更好（反之亦然）；HIV合并感染促进了HCV在不同血细胞类型中的复制。拟议的研究将是第一个同时评估肝脏和外周血中的抗HCV免疫反应及其对同一天从研究对象收集的血清、肝脏和血液中HCV复制和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.