Mechanisms of Hepatitis C Virus Evolution

丙型肝炎病毒进化机制

• 批准号: 7472551
• 负责人: STUART C RAY
• 金额: $ 50.31万
• 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/7472551
• 关键词: Acute; Affect; Alkaline Phosphatase; Amino Acids; Antigens; Appearance; Automobile Driving; Biological; CD8B1 gene; Chronic; Consensus Sequence; Cultured Cells; 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-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）：本项目的主要目的是通过研究从急性到慢性感染过渡期间的丙型肝炎病毒（HCV）序列，并检查驱动和限制病毒变异的潜在机制，来促进对体内病毒进化的理解。我们将测量体液和细胞宿主免疫应答，以及免疫驱动的变异对基本病毒酶活性的功能影响。这些结果将促进我们对宿主-病原体关系、免疫保护相关性和病毒逃避的理解。我们假设HCV的进化在很大程度上是决定性的。具体而言，随机（离散和随机产生的）突变通过选择过滤，这是由驱动（正选择）和约束（负选择）所得变化的可测量因素介导的。了解这些因素将有助于合理的疫苗设计，并指导HCV复制的小分子抑制剂的使用。我们提出以下目标：（1）确定细胞免疫应答在从急性感染向慢性感染转变过程中驱动HCV进化的作用;（2）研究慢性感染过程中HCV包膜基因的进化机制，以及HIV合并感染对HCV进化的影响，我们将研究HIV感染前后对HCV的体液应答，并与仔细匹配的对照受试者进行对照;为了研究免疫逃逸对病毒适应度的影响以及负选择的机制，我们将使用新的细胞培养和单轮HCV复制的亚基因组复制子模型来测量免疫驱动的变异对病毒复制适应度的影响。我们已经证明，我们可以获得在这项调查中所需的关键组织，进行独特的纵向研究的人从急性过渡到建立感染，测量细胞和体液免疫反应，并使用体外模型来阐明HCV的发病机制。因此，我们预计在这些独特的研究中成功的积极和消极的选择作用于感染剂在人类感染。