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

基本信息

批准号：
8037137
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
项目类别：
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/8037137
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 in vivo innovation liver transplantation novel research study resistance mechanism response viral resistance

项目摘要

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问题之一。目前，聚乙二醇干扰素-α加利巴韦林的最佳抗病毒治疗可治愈约 50% 的 HCV 基因型 1 感染患者和约 80% 的 HCV 基因型 2 和 3 感染患者。我们理解治疗耐药性的困难之一是相关的现有抗病毒药物的性质。干扰素和利巴韦林长期以来都以其广谱抗病毒活性而闻名，它们通过产生非特异性抗病毒状态而不是与病毒直接相互作用。因此，没有记录到 HCV 基因组的明确目标。对这些药物的耐药性研究通过传统方法产生了非常有争议的数据，这些方法经常关注 HCV 的短域而不是整个病毒基因组。利用新型长 RT-PCR 和克隆技术以及来自丙型肝炎抗病毒长期治疗肝硬化试验 (HALT-C) 的经过充分表征的血清样本，我们提出了一个病毒测序项目，通过该项目将了解抗病毒治疗的病毒机制。并在多个层面上进行详尽的审查。假设：HCV 对抗病毒治疗的耐药性与病毒准种在单一变异或群体水平上的区域依赖性突变有关。目标 1：探索感染 HCV 基因型 1a 的无效应答者在 HCV 分离株和准种水平上的遗传特征。基线的全长 HCV 准种谱将从具有无效或持续病毒学应答 (SVR) 的患者生成，然后进行比较分析，以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 在抗病毒治疗的高反应率方面是否存在独特的准种结构。全长 HCV 准种谱将从 20 个 HCV 基因型 2a 的 SVR 中生成，然后与 HCV 基因型 1a 衍生的 SVR 进行比较分析。目标 3：表征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。复发表明丙型肝炎病毒从抗病毒治疗下形成的假定群体瓶颈中存活了下来。 HCV如何应对这种“体内”群体瓶颈？该问题将通过对全长 HCV 准种概况进行连续比较分析来解决。这些研究的数据将立即应用于未来 HCV 抗病毒治疗的合理设计，其中 PegIFN-( 和利巴韦林仍然是核心成分。