HCV Genomic Variability in HIV Infected Hemophiliacs

有症状的血友病患者多次暴露于血液制品，包括因子浓缩物，以纠正互联网凝血因子缺乏症。在常规使用热灭活和筛选供体血液中的特定病毒病原体之前，血友病患者常规暴露于并感染B肝炎（HBV）、丙型肝炎（HCV）和人类免疫缺陷病毒（HIV）等病毒。血友病患者的队列研究提出了几个临床和科学上重要的发现，需要进一步详细的研究，包括：a）在感染HCV的血友病患者中，肝脏疾病进展可能会改变，更快地进展到肝衰竭和死亡; B）来自可能被多个谨慎供体感染的大型浓缩物池的感染源导致混合感染的高风险，基因型和准种异质性; c）HIV合并感染的血友病患者可能具有不同的临床结果，并且改变的免疫应答可能有助于我们理解突变病毒选择的潜在过程以及相关的临床结果。该提案的总体目标包括研究和表征感染血友病患者的HCV基因组RNA，无论是否与HIV一起食用甜食。在回顾性I期研究中，我们利用NCI多中心血友病队列研究血清库数据库研究进展至失代偿性肝病与病毒包膜高变区和核心区的准种属变异性之间的关系。异源双链体分析将用于使用10年或更长时间内纵向收集的样本快速筛选索引患者和匹配对照的样本。肽将从独特的准物种产生，并将评价这些肽作为CTL表位的功能。第2阶段包括临床干预试验的启动和执行，旨在确定单独HCV与HCV/HIV合并感染受试者的血友病患者对PEG-干扰素+利巴韦林的可变动力学应答率。将修饰/克隆准种群体，进行测序以产生密切相关的核心肽家族，研究其结合和刺激免疫应答的能力。治疗无应答者将在前瞻性队列研究中再随访3年，以便评估该组中病毒的演变及其相关的免疫应答。

Hemophiliacs with symptomatic disease are multiply exposed to blood products including factor concentrates to correct the Internet clotting factor deficiencies. Prior to routine use of heat inactivation and screening of donor blood for specific viral pathogens, hemophilia patients were routinely exposed to, and infected with, viruses such as hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV). Cohort studies in hemophiliacs suggest several clinically and scientifically important findings that warrant further detailed investigation including; a) Liver disease progression may be altered in hemophiliacs infected with HCV with more rapid progression to liver failure and death; b) The source of infection from large pools of concentrate that were potentially infected by multiple discreet donors leads to a high risks of mixed infection represented by both genotype and quasi species heterogeneity; c) The HIV coinfected hemophiliacs may have different clinical outcomes and an altered immune response may facilitate our understanding of the underlying process of mutant virus selection, and the associated clinical outcomes. The overall goals of this proposal include the study and characterization of the genomic RNA of HCV in infected hemophilic patients with and without confection with HIV. In the retrospective Phase 1, we utilize the NCI Multi center Hemophiliac Cohort Study serum bank database to study the relationship between progression to decompensated liver disease and quasi species variability in the viral envelope hyper variable and core domain. Heteroduplex analysis will be used to rapidly screen samples from index patients and matched controls using samples longitudinally collected over a 10 year or longer period of time. Peptides will be produced from unique quasi species and these peptides will be evaluated for their function as CTL epitomes. Phase 2 involves the initiation and performance of a clinical intervention trial designed to determine variable kinetic response rates to PEG-interferon+ribavirin between hemophiliacs with HCV alone vs HCV/HIV coinfected subjects. Quasi species populations will be modified/cloned, sequencing will be performed to generate families of closely related core peptides that will be studied for their ability to bind and stimulate an immune response. Treatment nonresponders will be followed in a prospective cohort study for up to 3 additional years so that the evolution of the virus, and its associated immune response in this group can be evaluated.