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)阳性个人也感染了丙型肝炎病毒(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的免疫控制。我们已经确定了与更严重的丙型肝炎相关的两个病毒学变量：丙型肝炎病毒准种(QS)的遗传变异性降低，以及感染肝脏内丙型肝炎病毒复制指数的增加。我们的初步研究表明，丙型肝炎病毒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，即在自然感染期间，丙型肝炎病毒在体内驻留在肝周淋巴结中的T淋巴细胞中能够产生复制，这表明了一种新的疾病机制。在这项竞争性更新申请中提出的研究将扩大我们对合并和不合并HIV感染的受试者慢性丙型肝炎病毒感染的病毒学和免疫学的关注。目的1将解决丙型肝炎病毒单一感染者和丙型肝炎病毒/艾滋病病毒混合感染者肝脏和外周血单核细胞内丙型肝炎病毒QS变异的组织区划。我们预测，HIV合并感染将导致外周血细胞中丙型肝炎病毒复制增加，PBMC限制性丙型肝炎病毒QS将成为血清相关丙型肝炎病毒QS的更主要组成部分。目的2将解决以下假设：1)肝内免疫反应与体内丙型肝炎病毒复制下调有关；2)宿主免疫反应驱动丙型肝炎病毒QS多样化；3)慢性丙型肝炎病毒感染时发生区段特异性免疫。目的3研究研究对象分离的丙型肝炎病毒QS在体外细胞培养中的传染性。这一目标将检验以下假设，即某些丙型肝炎病毒QS在造血细胞中固有地比肝细胞类型复制得更好(反之亦然)，以及HIV共同感染促进了丙型肝炎病毒在血细胞类型中的复制。这项拟议的研究将首次同时评估肝脏和外周血中的抗丙型肝炎病毒免疫反应及其对肝内丙型肝炎病毒复制和血清、肝脏和血液样本中丙型肝炎病毒QS变异性的影响。该研究还将检测HIV混合感染对体内丙型肝炎病毒-宿主生物学的影响以及体外组织培养中丙型肝炎病毒与艾滋病毒的相互作用，有助于我们理解联合感染如何加速丙型肝炎的发生。

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.