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

基因型

基本信息

批准号：
9267990
负责人：
JASON T BLACKARD
金额：
$ 29.94万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-02 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9267990
关键词：
AIDS/HIV problem Address Amino Acid Substitution Antiviral Agents Biochemical Biochemistry Chronic Hepatitis C Clinical Clinical Management Collaborations Data Development Disease Progression Drug resistance Epitopes Evolution Fibrosis Funding Genetic Genome Genotype HIV HIV therapy HIV/HCV Hepatitis Hepatitis C Immune Evasion Immune Targeting Immune response Immune system In Vitro Individual Infection Injecting drug user Liver diseases Medicine Mono-S Morbidity - disease rate Mutation National Institute of Drug Abuse Natural History New Agents Patients Persons Phenotype Polymerase Population Positioning Attribute Prevalence Property Proteins RNA RNA-Directed RNA Polymerase Reporting Research Resistance Risk Saints Structural Genes Structure Treatment outcome Universities Variant Viral Viral Genome Viral Load result Virus Virus Diseases Virus Replication Woman Work antiretroviral therapy co-infection college design epidemiology study improved in vivo inhibitor/antagonist liver development mortality novel pressure public health relevance research study resistance mutation treatment response viral RNA viral fitness virology virus genetics virus pathogenesis

项目摘要

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.

描述（由申请人提供）：丙型肝炎病毒（HCV）合并感染已成为艾滋病毒/艾滋病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 混合感染与 HCV 复制增强、纤维化增加以及肝病的发生有关。 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（例如 NS5B）受到不同的选择压力，即保留对病毒复制、耐药突变和/或补偿突变至关重要的酶功能所必需的纯化选择。尽管 NS5B 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，有关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 复制和发病机制理解上的巨大差距，我们建议对两个特征明确的 HCV 和/或 HIV 合并感染人群中的 NS5B 基因型、表型和生化变异进行全面分析。此类研究对于促进新型 HCV 疗法的合理设计和利用以及显着改善慢性 HCV 感染者的临床管理和总体生存至关重要。