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: 8242874
• 负责人: XIAOFENG FAN
• 金额: $ 28.81万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242874
• 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; Yin; comparative; design; drug withdrawal; innovation; liver transplantation; new technology; novel; research study; resistance mechanism; response; success; viral resistance

Project Summary 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. Project Narrative Hepatitis C virus infection is one of the major concerns in public health and current antiviral therapy has very differential success within and among HCV genotypes. We will examine viral determinants responsible for the treatment resistance through the application of novel technology. This may help to design more effective antiviral therapy to chronic HCV infection.

项目摘要 丙型肝炎病毒（HCV）感染是公共卫生的主要关注点之一。目前，最佳抗病毒 用叶甲状干扰素-alpha加上利巴韦林治疗，治愈了约50％的感染HCV基因型1的患者 在感染HCV基因型2和3的患者中，约有80％的患者关于我们的困难之一 对治疗耐药性的了解与当前抗病毒剂的性质有关。两个干扰素 长期以来，利巴韦林以其广谱抗病毒活性而闻名 抗病毒状况，而不是与病毒直接相互作用。因此，HCV没有明确的目标 基因组已被记录。这些药物的耐药性研究已经非常非常 通过常规关注HCV短域的常规方法，有争议的数据 而不是整个病毒基因组。使用新颖的长RT-PCR和克隆技术和良好的 来自丙型肝炎抗病毒长期治疗的血清样品表征了针对肝硬化试验的血清样品 （Halt-C），我们提出了一个病毒测序项目 抗病毒疗法将在多个级别进行详尽检查。 假设：抗病毒治疗的HCV抗性与区域依赖性突变有关 单个变体或人口水平的病毒准菜。 目的1：在无效响应者的HCV分离株和准级别上探索遗传特征 感染HCV基因型1a。将生成基线上的全长HCV准佩克斯轮廓 来自无效或持续病毒反应（SVR）的患者，然后进行比较分析 确定与治疗耐药性相关的潜在遗传特征。 目标2：证明HCV基因型2是否存在不同的准菜结构 对抗病毒疗法的缓解率。将从 HCV基因型2a的二十SVR，然后进行比较分析与HCV的比较分析 基因型1a。 AIM 3：表征与HCV重新出现相关的突变模式。 对抗病毒疗法的初步反应。继电器表明HCV从推定的人群中生存 在抗病毒疗法下形成的瓶颈。 HCV对这种体内种群瓶颈有何反应？ 该问题将通过对全长HCV准佩斯的顺序比较分析来解决 概况。 这些研究的数据将立即应用于未来HCV抗病毒疗法的合理设计 在哪个pegifn-？利巴韦林仍然是核心组成部分。项目叙述 丙型肝炎病毒感染是公共卫生的主要关注点之一，当前的抗病毒药疗法已有 HCV基因型内部和之间的成功差异很大。我们将检查病毒确定负责 通过应用新技术来治疗耐药性。这可能有助于设计更多 慢性HCV感染的有效抗病毒疗法。

项目成果

Enhanced protocol for determining the 3' terminus of hepatitis C virus.

用于确定丙型肝炎病毒 3 末端的增强方案。

• DOI: 10.1016/j.jviromet.2010.03.030
• 发表时间: 2010
• 期刊: Journal of virological methods
• 影响因子: 3.1
• 作者: Zhang,Xiaoan;Fan,Xiaofeng;Xu,Yanjuan;DiBisceglie,AdrianM
• 通讯作者: DiBisceglie,AdrianM

Efficient amplification and cloning of near full-length hepatitis C virus genome from clinical samples.

• DOI: 10.1016/j.bbrc.2006.06.039
• 发表时间: 2006-08-11
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Fan X;Xu Y;Di Bisceglie AM
• 通讯作者: Di Bisceglie AM

Comprehensive cloning of patient-derived 9022-bp amplicons of hepatitis C virus.

全面克隆患者来源的丙型肝炎病毒 9022 bp 扩增子。

• DOI: 10.1016/j.jviromet.2013.04.010
• 发表时间: 2013
• 期刊: Journal of virological methods
• 影响因子: 3.1
• 作者: Lu,Yang;Xu,Yanjuan;DiBisceglie,AdrianM;Fan,Xiaofeng
• 通讯作者: Fan,Xiaofeng

High diversity of hepatitis C viral quasispecies is associated with early virological response in patients undergoing antiviral therapy.

• DOI: 10.1002/hep.23290
• 发表时间: 2009-12
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Fan, Xiaofeng;Mao, Qing;Zhou, Donghui;Lu, Yang;Xing, Jianwei;Xu, Yanjuan;Ray, Stuart C.;Di Bisceglie, Adrian M.
• 通讯作者: Di Bisceglie, Adrian M.

Divergent quasispecies evolution in de novo hepatitis C virus infection associated with bone marrow transplantation.

• DOI: 10.1016/j.bbrc.2011.09.041
• 发表时间: 2011-10-14
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Wang, Weihua;Lin, Jianguo;Tan, De;Xu, Yanjuan;Brunt, Elizabeth M.;Fan, Xiaofeng;Di Bisceglie, Adrian M.
• 通讯作者: Di Bisceglie, Adrian M.