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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

基本信息

批准号：
10378499
负责人：
Kwonil Jung
金额：
$ 18.52万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378499
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 Organism Outcome Pathogenesis Pathologic Pathology Patient-Focused Outcomes Patients Persons 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 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 recipient organ transplant rejection pathogen porcine model resistant strain response

项目摘要

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养猪项目摘要/摘要