Role of HCV Sequence Variation in Pathology

描述（由申请人提供）： 慢性丙型肝炎病毒（HCV）感染可引起肝炎、肝硬化、肝衰竭和肝细胞癌。控制沿着该病理谱的疾病进展速率的因素尚不清楚。HCV在遗传上是高度可变的，并且遗传变异是许多病毒性疾病中毒力的主要贡献者。HCV感染用聚乙二醇干扰素（加利巴韦林）治疗，但在美国最常见的基因型1型患者中，有一半失败。为了确定长期使用干扰素是否可以减缓治疗失败患者的疾病进展，NIDDK正在赞助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。由于其非常大的，特征良好的队列，HALT-C提供了一个独特的机会来研究HCV的遗传多样性如何影响疾病的进展。 假设：影响免疫逃避活动的HCV序列的遗传变异调节肝病进展的速度。 目的1：确定HCV序列变异如何与疾病进展相关。HCV诱导的肝脏疾病预计会受到病毒序列变异的影响，这些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例HALT-C患者中对完整的HCV ORF进行测序，并在3.25年后再次使用我们为Virahep-C临床研究开发的遗传方法。如HALT-C终点所定义，缓慢进展者将具有最小的疾病进展，而快速进展者将是具有重大疾病进展的患者。所有患者均来自HALT-C的未治疗组，以评估疾病的自然进展。将比较各组的病毒序列，以确定是否存在与疾病进展相关的病毒遗传模式，并表征病毒进化。 目的2：确定HCV基因变异如何影响病毒毒力调节蛋白的功能。影响HCV抵抗免疫系统能力的病毒蛋白质的变异可以调节发病机制。因此，将克隆来自缓慢和快速进展者的变异病毒基因，其中遗传变异与疾病进展相关，并测量其提出的促进毒力的生化活性。 这项研究将提供一个全面的分析的作用，在丙型肝炎病毒编码区的变化对肝脏疾病的进展。这将通过识别与疾病进展差异相关的病毒基因来深入了解病理机制。最后，这些研究可以确定预测疾病快速进展的病毒基序。

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.