Genotypic& phenotypic characterization of the HCV polymerase (NS5B) in HIV

描述（由申请人提供）：丙型肝炎病毒（HCV）合并感染已成为HIV/AIDS患者发病和死亡的主要原因。流行病学研究清楚地表明，HIV/HCV合并感染与HCV复制增强、纤维化增加和肝脏疾病的发展相关。HIV还增加了HCV结构基因的准种多样性。然而，与结构基因组区域相比，HCV基因组的非结构区域如NS 5 B受到不同的选择压力-纯化选择对于保留对病毒复制、耐药性突变和/或补偿突变至关重要的酶功能是必要的。尽管NS 5 B作为HCV治疗的新兴靶点越来越重要，但在缺乏直接作用疗法的情况下，关于其基因型变异性和表型特性的数据有限。到 为了解决我们对HCV复制和发病机制的理解中的这一巨大差距，我们提出了一个全面的分析NS 5 B基因型，表型和生化变异性在两个良好的特征人群与HCV和/或HIV共感染。这些研究对于促进新型HCV治疗的合理设计和利用以及显著改善慢性HCV感染者的临床管理和总体生存至关重要。

DESCRIPTION (provided by applicant): Co-infection with hepatitis C virus (HCV) has emerged as a major cause of morbidity and mortality for persons living with HIV/AIDS. Epidemiologic studies clearly indicate that HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes. However, non-structural regions of the HCV genome such as NS5B are subject to distinct selection pressures - purifying selection necessary to preserve enzymatic functions critical for viral replication, drug resistance mutations, and/or compensatory mutations - compared to structural genome regions. Despite the growing importance of NS5B as an emerging target of HCV therapy, limited data are available regarding its genotypic variability and phenotypic properties in the absence of directly acting therapies. To address this substantial gap in our understanding of HCV replication and pathogenesis, we propose a comprehensive analysis of NS5B genotypic, phenotypic, and biochemical variability in two well-characterized populations with HCV and/or HIV co-infection. Such studies are critical to facilitate the rational design and utilization of novel HCV therapies and significantly improve the clinical management and overall survival of persons with chronic HCV infection.