Role of HCV Sequence Variation in Pathology

描述(由申请人提供)： 慢性丙型肝炎病毒(丙型肝炎病毒)感染会导致肝炎、肝硬化、肝功能衰竭和肝细胞癌。沿着这一病理谱系控制疾病进展的因素尚不清楚。丙型肝炎病毒在基因上是高度可变的，在许多病毒性疾病中，基因变异是毒力的主要贡献因素。丙型肝炎病毒感染可用聚乙二醇化干扰素(加利巴韦林)治疗，但在美国最常见的1型患者中有一半无效。为了确定治疗失败的患者的疾病进展是否可以通过长期使用干扰素来减缓，NIDDK赞助了HALT-C临床研究。这些患者中有一半正在接受干扰素治疗，另一半是未经治疗的对照组。HALT-C是研究丙型肝炎病毒基因多样性如何影响疾病进展的独特机会，因为它具有非常大的特征。 假设：影响免疫逃避活动的丙型肝炎病毒序列的遗传变异调节了肝病的进展速度。 目的1：确定丙型肝炎病毒序列变异与疾病进展的关系。丙型肝炎病毒引起的肝病预计会受到病毒序列变异的影响，病毒序列变异通过改变逃避宿主抗病毒反应的能力来调节毒力。因此，我们将在两组20名HALT-C患者中对完整的丙型肝炎病毒ORF进行测序，并在3.25年后使用我们为Virahep-C临床研究开发的遗传方法再次测序。慢进者将有最小的疾病进展，而快速进展者将是根据HALT-C终点定义的疾病有较大进展的患者。所有患者都将来自HALT-C未经治疗的手臂，以评估疾病的自然进展。来自这些组织的病毒序列将进行比较，以确定是否存在与疾病进展相关的病毒遗传模式，并表征病毒的进化。 目的2：确定丙型肝炎病毒基因变异对病毒毒力调节蛋白功能的影响。影响丙型肝炎病毒中和免疫系统能力的病毒蛋白的变异可能调节发病机制。因此，来自慢速和快速进展者的变异病毒基因将被克隆，其中遗传变异与疾病进展相关，并将测量它们被提议促进毒力的生化活性。 这项研究将全面分析丙型肝炎病毒编码区变异在肝病进展中的作用。这将通过识别与疾病进展相关的病毒基因来洞察病理机制。最后，这些研究可能确定预测疾病快速发展的病毒基序。

DESCRIPTION (provided by applicant): Chronic Hepatitis C virus (HCV) infection causes hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. The factors governing the rate of disease progression along this spectrum of pathology are not known. HCV is highly variable genetically, and genetic variation is a major contributor to virulence in many viral diseases. HCV infection is treated with pegylated interferon ( plus ribavirin, but this fails in half of genotype 1 patients, the most common genotype in the USA. To determine if disease progression in patients who fail therapy can be slowed by long-term use of interferon (, the NIDDK is sponsoring the HALT-C clinical study. Half of these patients are receiving interferon and half are untreated controls. Because of its very large, well-characterized cohort, HALT-C presents a unique opportunity to study how HCV's genetic diversity affects disease progression. Hypothesis: Genetic variation in HCV sequences affecting immune evasion activities modulates the rate of progression of liver disease. Aim 1: Determine how HCV sequence variation is associated with disease progression. HCV induced liver disease is predicted to be influenced by viral sequence variations that modulate virulence through altering the ability to evade host antiviral responses. Therefore, we will sequence the complete HCV ORF in two groups of 20 HALT-C patients and again 3.25 years later employing genetic approaches we developed for the Virahep-C clinical study. Slow Progressors will have minimal disease progression and Rapid Progressors will be patients with major advancement of disease, as defined by the HALT-C endpoints. All patients will be from the untreated arm of HALT-C to assess natural progression of disease. Viral sequences from the groups will be compared to determine if there are viral genetic patterns correlating with disease progression and to characterize viral evolution. Aim 2: Determine how HCV genetic variation affects function of viral proteins implicated in modulating virulence. Variation in viral proteins that affect the ability of HCV to counteract the immune system could modulate the pathogenesis. Therefore, variant viral genes from slow and rapid progressors in which genetic variation correlates with disease progression will be cloned and their biochemical activities proposed to promote virulence will be measured. This study will provide a comprehensive analysis of the role of variation in the HCV coding region on progression of liver disease. This will yield insight into the mechanism of pathology by identifying viral genes associated with differences in disease progression. Finally, these studies may identify viral motifs predictive of rapid disease advancement.