Evaluating hepatitis E virus ribavirin resistance clinical outcomes in the immunosuppressed pig model

评估免疫抑制猪模型中戊型肝炎病毒利巴韦林耐药的临床结果

• 批准号: 10116651
• 负责人: Kwonil Jung
• 金额: $ 22.48万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116651
• 关键词: Acute Disease; Acute Liver Failure; Animal Model; Autopsy; Biochemical; Biological Models; CD8-Positive T-Lymphocytes; Cessation of life; Chronic; Chronic Hepatitis; Clinical; Country; Developed Countries; Developing Countries; Disease; Dose; Drug resistance; Escape Mutant; Evolution; Exhibits; Family suidae; Frequencies; Future; Goals; Growth; HIV; Health; Hepatitis E; Hepatitis E virus; Human; Immune response; Immunocompetent; Immunocompromised Host; Immunologic Factors; In Vitro; Individual; Infection; Integration Host Factors; Interferon Type II; Interleukin-10; Interleukin-17; Interleukin-4; Lead; Lesion; Life; Liver; Liver Failure; Measures; Mission; Modeling; Morbidity - disease rate; Mutation; Organ Transplantation; Organism; Outcome; Pathogenesis; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Play; Prevalence; RPS19 gene; Recombinants; Regulatory T-Lymphocyte; Reporting; Resistance; Ribavirin; Ribosomal Proteins; Role; Sampling; Severity of illness; Single Nucleotide Polymorphism; Solid; System; T cell response; T-Cell Proliferation; Testing; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factor beta; Transplant Recipients; Treatment Failure; United States; United States National Institutes of Health; Variant; Viral; Viral Load result; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Zoonoses; cytokine; deep sequencing; disability; immunosuppressed; in vivo; insight; leukemia/lymphoma; mortality; mutant; novel; organ transplant rejection; pathogen; porcine model; resistant strain; response; virology

RBV Pig Project Summary/Abstract Hepatitis E virus (HEV) is an emerging zoonotic pathogen endemic in both developing countries and in developed countries including the United States (U.S.). HEV infects 20 million individuals annually, resulting in 3.3 million symptomatic cases with 44,000 deaths. In countries like the U.S., HEV prevalence is being recognized as a danger to immunocompromised individuals where the virus becomes chronic and can result in acute liver failure among other consequences. Approximately 58-92% of HEV-infected organ transplant recipients developed chronic HEV infection. Currently the recommended treatment for chronic HEV is ribavirin (RBV). There have already been clinical cases where RBV has failed to clear HEV infection, resulting in poor patient outcome. RBV treatment failure has been attributed to single nucleotide variant (SNV) HEV strains that can be circulating as quasispecies in the host that have shown resistance to RBV and/or enhanced replication. Furthermore, long- term replication of HEV in the chronically infected host has led to the identification of viral quasispecies that contained insertions of host ribosomal protein S17 (RPS17) or S19 (RPS19) sequences also leading to enhanced viral replication and increased host range. How naturally occurring HEV variants with enhanced replication, such as those harboring RPS17 or single nucleotide variants, contribute to viral pathogenesis is currently unknown. The immediate goal of this project is to adapt the existing immunosuppressed pig chronic HEV system to model RBV treatment failure and resulting disease severity due to variant HEV strains. In specific aim 1, we hypothesize that the immunosuppressed swine model in conjunction with suboptimal RBV treatment will mimic patient treatment in the clinical setting resulting in novel HEV variants and enhanced disease pathogenesis. To test this hypothesis, we will experimentally infect immunosuppressed pigs with wild type HEV or variant HEV, treating some groups with RBV. We can then sequence resulting HEV variants and compare disease severity between variant and wild type HEV groups. In specific aim 2, we hypothesize that SNV variants exhibiting enhanced growth potential in vitro will correlate to enhanced disease in vivo in part due to differential host immune responses. To test this hypothesis, we will characterize the immune response in pigs infected with wild type HEV, and variant HEV viruses from samples collected during specific aim 1. The long- term goal of this project is to determine viral and host interactions that dictate the outcome of infection by HEV and develop strategies and therapeutics that can mitigate poor outcomes. The results from this R21 will be important for future in-depth mechanistic studies of host factors in HEV infection, especially chronic and cross- species infection. Our specific aims and long-term objectives align well with NIH mission goals seeking to enhance health, lengthen life, and reduce illness and disability through understanding viral factors contributing to liver failure and solid organ transplant rejection.

RBV 猪项目总结/摘要 戊型肝炎病毒（HEV）是一种新兴的人畜共患病病原体，在发展中国家和发达国家均流行。 包括美国（U.S.）在内的国家。 HEV 每年感染 2000 万人，导致 330 万人死亡 有症状的病例导致 44,000 人死亡。在美国等国家，HEV 的流行被认为是一个 当病毒变成慢性病毒并可能导致急性肝功能衰竭时，对免疫功能低下的个体构成危险 除其他后果外。大约 58-92% 感染 HEV 的器官移植受者发育成功 慢性HEV感染。目前推荐的慢性 HEV 治疗方法是利巴韦林 (RBV)。有 RBV 未能清除 HEV 感染的临床案例已经存在，导致患者预后不佳。 RBV 治疗失败归因于单核苷酸变异 (SNV) HEV 毒株，该毒株可作为 宿主中的准种已表现出对 RBV 的抗性和/或增强的复制。此外，长 HEV 在慢性感染宿主体内的长期复制导致了病毒准种的鉴定， 含有宿主核糖体蛋白 S17 (RPS17) 或 S19 (RPS19) 序列的插入，也导致 增强病毒复制并增加宿主范围。天然存在的 HEV 变种如何具有增强功能 复制，例如那些含有 RPS17 或单核苷酸变体的复制，有助于病毒发病机制 目前未知。该项目的近期目标是适应现有的免疫抑制猪慢性病 HEV 系统可模拟 RBV 治疗失败以及由于 HEV 变异株导致的疾病严重程度。具体来说 目标 1，我们假设免疫抑制猪模型与次优 RBV 治疗相结合 将模仿临床环境中的患者治疗，从而产生新的 HEV 变异并增强疾病 发病。为了验证这一假设，我们将通过实验用野生型 HEV 感染免疫抑制的猪 或变异 HEV，用 RBV 治疗某些组。然后我们可以对所得的 HEV 变体进行测序并进行比较 变异型和野生型 HEV 群体之间的疾病严重程度。在具体目标 2 中，我们假设 SNV 在体外表现出增强的生长潜力的变体将与体内疾病的增强相关，部分原因是 不同的宿主免疫反应。为了检验这个假设，我们将描述猪的免疫反应 感染了野生型HEV，以及在特定目标1期间收集的样本中的变种HEV病毒。 该项目的长期目标是确定决定 HEV 感染结果的病毒和宿主相互作用 并制定可以减轻不良结果的策略和疗法。 R21 的结果将是 对于未来对 HEV 感染宿主因素的深入机制研究非常重要，尤其是慢性和交叉感染 种感染。我们的具体目标和长期目标与 NIH 的使命目标高度契合，旨在 通过了解病毒因素，增强健康、延长寿命、减少疾病和残疾 肝衰竭和实体器官移植排斥反应。