Mechanisms of Hepatitis C Virus Evolution

丙型肝炎病毒进化机制

• 批准号: 7904927
• 负责人: STUART C RAY
• 金额: $ 52.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904927
• 关键词: Acute; Affect; Alkaline Phosphatase; Amino Acids; Antigens; Appearance; Automobile Driving; Biological; CD8B1 gene; Cell Culture Techniques; Chronic; Consensus Sequence; Emigrant; Epitopes; Escape Mutant; Evolution; Failure; Genes; Genome; Growth; HIV; HIV Infections; Hepatitis C virus; Human; Immune; Immune response; Immunotherapy; In Vitro; Infection; Infectious Agent; Investigation; Longitudinal Studies; Measurable; Measures; Mediating; Modeling; Mutation; Noise; Persons; Population; Relative (related person); Replicon; Research Personnel; Role; Signal Transduction; System; T cell response; T-Lymphocyte; Techniques; Therapeutic; Tissues; Vaccine Design; Vaccines; Variant; Viral; Viral Proteins; Virus Replication; anti-hepatitis C; base; design; enzyme activity; fitness; immunogenicity; in vitro Model; in vivo; inhibitor/antagonist; insight; mutant; novel; pathogen; pressure; protein protein interaction; response; small molecule; success; viral RNA; virus pathogenesis

DESCRIPTION (provided by applicant): The primary objective of this project is to advance understanding of viral evolution in vivo by studying hepatitis C virus (HCV) sequences during the transition from acute to chronic infection, and examining the underlying mechanisms that drive and constrain viral variation. We will measure humoral and cellular host immune responses, as well as the functional impact of immune-driven variation on essential viral enzyme activities. The results will advance our understanding of the host-pathogen relationship, correlates of immune protection, and viral evasion. We hypothesize that HCV evolution is largely deterministic. Specifically, stochastic (discrete and randomly-generated) mutations are filtered by selection, which is mediated by measurable factors that both drive (positive selection) and constrain (negative selection) the resulting variation. Understanding these factors will facilitate rational vaccine design, and guide the use of small-molecule inhibitors of HCV replication. We propose the following aims: (1) to determine the role of the cellular immune response in driving HCV evolution during the transition from acute to chronic infection; (2) to investigate the mechanisms for evolution in the envelope genes of HCV during chronic infection, and the effects of HIV co-infection on HCV evolution, we will study humoral responses to HCV before and after HIV infection, with carefully-matched control subjects; and (3) to investigate the impact of immune escape on viral fitness and the mechanisms of negative selection, we will measure the impact of immune-driven variation on viral replicative fitness, using novel cell culture and single-round subgenomic replicons models of HCV replication. We have already demonstrated that we can obtain the critical tissues required in this investigation, conduct unique longitudinal studies of persons transitioning from acute to established infection, measure cellular and humoral immune responses, and use in vitro models to elucidate HCV pathogenesis. Therefore, we anticipate success in these unique studies of positive and negative selection acting on an infectious agent during human infection.

描述（由申请人提供）：该项目的主要目的是通过研究从急性感染到慢性感染的过渡过程中研究丙型肝炎病毒（HCV）序列，并检查驱动和约束病毒变异的基本机制，以提高对体内病毒进化的了解。我们将测量体液和细胞宿主免疫反应，以及免疫驱动变异对必需病毒酶活性的功能影响。结果将提高我们对宿主病原关系，免疫保护的相关性和逃避病毒的理解。我们假设HCV进化在很大程度上是确定性的。具体而言，随机（离散和随机生成的）突变是通过选择过滤的，这是由可测量因素介导的，这些因素均可驱动（正选择）和约束（负选择）所得的变化。了解这些因素将有助于理性疫苗设计，并指导使用小分子抑制剂HCV复制的使用。我们提出以下目的：（1）确定细胞免疫反应在从急性到慢性感染过渡过程中驱动HCV演化中的作用； （2）研究慢性感染期间HCV包膜基因进化的机制，以及HIV共感染对HCV进化的影响，我们将研究对HIV感染前后对HCV的体液反应，并具有仔细匹配的对照组受试者； （3）为了研究免疫逃逸对病毒适应性的影响和负选择的机制，我们将使用新型的细胞培养和HCV复制的单回合亚基因组复制剂模型来衡量免疫驱动变异对病毒复制适应性的影响。我们已经证明，我们可以在这项研究中获得所需的关键组织，对从急性感染到既定感染的人进行独特的纵向研究，测量细胞和体液免疫反应，并使用体外模型阐明HCV发病机理。因此，我们预计在这些在人类感染期间对阳性和负面选择作用于感染剂的独特研究将取得成功。