Viral Host Interactions in Hepatitis C

描述(申请人提供)：尽管慢性丙型肝炎的发病机制尚不清楚，但最近的研究表明，发生在丙型肝炎病毒和受感染宿主之间的动态相互作用是病毒持续和疾病进展的关键决定因素。在人类身上的研究表明，丙型肝炎病毒的遗传进化形成病毒准种，宿主对丙型肝炎病毒抗原的CD4和CDS应答的强度都与感染的持续和慢性肝病的进展密切相关。然而，需要进行研究，证实丙型肝炎病毒的进化和个别患者的免疫反应之间存在直接的相互作用，并产生特定的结果。这项建议的总体目标是通过研究丙型肝炎病毒基因进化和宿主免疫反应之间的关系来更好地了解丙型肝炎的发病机制，因为它们与感染的解决或持续以及慢性肝病的进展或不进展有关。我们将研究阿拉斯加原住民和美洲印第安人队列中的受试者，利用可追溯到30多年前的血清库和过去8年中编辑的约1000名受试者的大型临床和病毒学数据库。丙型肝炎病毒的遗传进化将在不同临床环境下宿主免疫反应的背景下进行研究。这些研究的结果将进一步加深我们对丙型肝炎持续和肝病进展机制的理解。

DESCRIPTION (provided by applicant): Although the pathogenesis of chronic hepatitis C is poorly understood, recent studies implicate the dynamic interactions which occur between HCV and the infected host as key determinants of viral persistence and disease progression. Studies in humans indicate that genetic evolution of HCV to form viral quasispecies, and the strength of host CD4 and CDS response against HCV antigens are both critically linked to persistence of infection and progression of chronic liver disease. However, research confirming a direct interplay between HCV evolution and the immune responses of individual patients with specific outcomes needs to be performed. The overall goal of this proposal is to gain a better understanding of the pathogenesis of hepatitis C by investigating the relationships between HCV genetic evolution and host immune responses as they relate to resolution or persistence of infection and progression or non- progression of chronic liver disease. We will study subjects from the Alaska Native and American Indian cohort, taking advantage of a serum bank which dates back over 30 years and a large clinical and virological database compiled on approximately 1000 subjects over the past 8 years. HCV genetic evolution will be studied in the context of host immune responses in different clinical settings. Results from these studies will further our understanding of the mechanisms of HCV persistence and liver disease progression.