Hepatitis C Virus Quasispecies in the Resistance to Antiviral Therapy

丙型肝炎病毒准种对抗病毒治疗的耐药性

• 批准号: 7774317
• 负责人: XIAOFENG FAN
• 金额: $ 29.33万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774317
• 关键词: Acute Hepatitis C; Address; American; Antiviral Agents; Antiviral Therapy; Appearance; Behavior; Biology; Cessation of life; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Cloning; Consensus Sequence; Data; Detection; Drug resistance; Experimental Models; Extinction (Psychology); Future; Genetic; Genetic Recombination; Genome; Genotype; Hepatitis C; Hepatitis C Antiviral; Hepatitis C virus; Infection; Integration Host Factors; Interferons; Length; Mutation; Nature; Patients; Pattern; Pegylated Interferon Alfa; Play; Population; Population Study; Public Health; Relapse; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Ribavirin; Role; Sampling; Serum; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; United States; Variant; Viral; Viral Drug Resistance; Viral Genome; Virus; comparative; design; drug withdrawal; in vivo; innovation; liver transplantation; novel; research study; resistance mechanism; response; viral resistance

DESCRIPTION (provided by applicant):Hepatitis C virus (HCV) infection is one of the major concerns in public health. Currently, optimal antiviral therapy with pegylated interferon-alpha plus ribavirin, cures ~50% of patients infected with HCV genotype 1 and ~80% of patients infected with HCV genotypes 2 and 3. One of the difficulties regarding our understanding on treatment resistance is related to the nature of current antiviral agents. Both interferon and ribavirin have long been known for their broad-spectrum antiviral activity by creating a non-specific antiviral status rather than the direct interaction with viruses. Consequently, no explicit targets on HCV genome have been documented. Studies on drug resistance with these agents have generated very controversial data through conventional approaches that frequently focus on short domains of the HCV rather than the entire viral genome. Using a novel long RT-PCR and cloning technology and well characterized serum samples from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial (HALT-C), we propose a viral sequencing project through which viral mechanisms for the resistance to antiviral therapy will be exhaustively examined at multiple levels. HYPOTHESIS: HCV resistance to antiviral therapy is associated with region-dependent mutations of viral quasispecies at either single variants or the population level. Aim 1: To explore genetic signatures at both HCV isolate and quasispecies levels in null responders infected with HCV genotype 1a. The full-length HCV quasispecies profiles at the baseline will be generated from patients with either null or sustained virological responses (SVR), followed by comparative analyses to identify potential genetic signatures that are associated with the treatment resistance. Aim 2: To demonstrate if there are distinct quasispecies structures of HCV genotype 2 in terms of the high response rate to the antiviral therapy. The full-length HCV quasispecies profiles will be generated from twenty SVRs with HCV genotype 2a, followed by comparative analyses with those derived from HCV genotype 1a. Aim 3: To characterize mutational patterns associated with HCV re-emergence in patients with relapse after initial response to antiviral therapy. The relapse indicates the survival of HCV from a putative population bottleneck formed under antiviral therapy. How does HCV respond to such "in vivo" population bottlenecks? This issue will be addressed through a sequential comparative analysis of full-length HCV quasispecies profiles. Data from these studies will have immediate applications for rational design of future HCV antiviral therapy in which PegIFN-( and ribavirin are still the core components.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染是公共卫生的主要关注点之一。目前，使用卵甲化干扰素 - α和利巴韦林的最佳抗病毒疗法治疗，感染了HCV基因型1和感染HCV基因型2和3的患者中约有50％的患者被感染。我们对治疗耐药性的困难之一与当前抗病毒抗病毒药物的性质有关。长期以来，干扰素和利巴韦林一直以其广谱抗病毒活性而闻名，它通过创建非特异性抗病毒状态而不是与病毒的直接相互作用而闻名。因此，尚未记录关于HCV基因组的明确靶标。对这些药物的耐药性研究已经通过常规方法引起了非常有争议的数据，这些方法经常集中在HCV的短域而不是整个病毒基因组上。使用新型的长RT-PCR和克隆技术以及来自肝炎抗病毒长期治疗针对肝硬化试验（HALT-C）的血清样品，我们提出了一个病毒测序项目，通过该项目，将在多个层面上详尽地检查了抗病毒治疗的病毒机制。 假设：HCV对抗病毒疗法的抗性与单个变体或种群水平的病毒准蛋白的区域依赖性突变有关。 目标1：探索在HCV分离株和准响应者中均感染HCV基因型1a的遗传特征。基线上的全长HCV准剖分谱将由无效或持续病毒反应（SVR）的患者产生，然后进行比较分析，以识别与治疗耐药性相关的潜在遗传特征。 目的2：证明HCV基因型2是否存在明显的准基因结构，就抗病毒疗法的高反应率而言。全长HCV准剖分曲线将来自具有HCV基因型2a的20个SVR，然后进行比较分析，该分析与HCV基因型1a的分析。 AIM 3：表征与抗病毒治疗初始反应后复发患者中与HCV重新出现相关的突变模式。复发表明，在抗病毒疗法下形成的假定种群瓶颈HCV的生存。 HCV如何应对这种“体内”人口瓶颈？ 该问题将通过对全长HCV准剖分曲线的顺序比较分析来解决。这些研究的数据将在未来的HCV抗病毒疗法的合理设计中立即应用，其中PEGIFN-（和利巴韦林仍然是核心成分。