HCV Genomic Variability in HIV Infected Hemophiliacs

有症状疾病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陷。在常规使用热灭活和对献血者血液进行特定病毒病原体筛查之前，血友病患者常规暴露于并感染乙肝（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一些临床和科学上重要的发现，值得进一步的详细调查，包括；a)感染HCV的血友病患者的肝脏疾病进展可能发生改变，更迅速地进展为肝衰竭和死亡；b)感染源来自可能被多个谨慎的供体感染的大型浓缩池，导致以基因型和准物种异质性为代表的混合感染的高风险；c) HIV合并感染的血友病患者可能有不同的临床结果，免疫反应的改变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。本提案的总体目标包括研究和表征感染的血友病患者的HCV基因组RNA，并与不与HIV合并。在回顾性一期研究中，我们利用NCI多中心血友病队列研究血清库数据库来研究失代偿性肝病的进展与病毒包膜超变量和核心域的准物种变异性之间的关系。异双工分析将用于快速筛选指数患者和匹配对照的样本，使用纵向收集的样本超过10年或更长时间。多肽将从独特的准物种中产生，这些多肽将被评估其作为CTL表集的功能。第二阶段涉及临床干预试验的启动和执行，旨在确定单独HCV与HCV/HIV合并感染的血友病患者对peg -干扰素+利巴韦林的可变动力学反应率。准物种群体将被修改/克隆，测序将被执行，以产生密切相关的核心肽家族，将研究其结合和刺激免疫反应的能力。在一项前瞻性队列研究中，将对治疗无反应者进行长达3年的随访，以便对该组中病毒的演变及其相关免疫反应进行评估。

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.