Hepatitis B virus immune escape mutants

乙型肝炎病毒免疫逃逸突变体

基本信息

批准号：
7470857
负责人：
SHUPING TONG
金额：
$ 14.58万
依托单位：
RHODE ISLAND HOSPITAL
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：
2008-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470857
关键词：
Accounting Affinity Amino Acid Substitution Amino Acids Antibodies Antibody Affinity Biological Blood Blood Circulation Cancer Vaccines Cell Line Cells Child Childhood Cirrhosis Collaborations Containment Defect Drug resistance Epidemiologic Studies Epitopes Escape Mutant Future Genes Genome Hepatitis Hepatitis B Hepatitis B Surface Antigens Hepatitis B Vaccines Hepatitis B Virus Human Immune Immune Sera Immune response Immunization Immunoglobulins Incidence Infection Knowledge Lamivudine Life Cycle Stages Link Liver diseases Malignant neoplasm of liver Mutation Nature Nucleosome Core Particle Overlapping Genes Pan Genus Pan troglodytes Patients Polymerase Polymerase Gene Prevention Primary carcinoma of the liver cells Prophylactic treatment Public Health RNA-Directed DNA Polymerase Rate Recurrence Reporting Resistance Risk Serum Simian B disease Site Staging Survival Rate Taiwan Testing Transfection Vaccination Vaccines Variant Viral Viral Envelope Proteins Virion Virus Virus Diseases design env Gene Products glycosylation graft failure hepatoma cell liver transplantation mutant neutralizing antibody novel nucleoside analog particle passive prophylaxis prevent programs prototype research study transmission process virus envelope

项目摘要

DESCRIPTION (provided by applicant): Nearly 400 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at risk for cirrhosis or liver cancer, which necessitates liver transplantation. Immunization with HBV envelope proteins prevents HBV infection, and hepatitis B immune globulin (HBIG), alone or together with nucleoside analogs such as lamivudine, reduces the re- infection rate of the grafted liver. However, breakthrough infection can occur in both vaccine recipients and liver graft recipients due to the emergence of neutralization escape mutants, often together with small amounts of wild-type virus. Such mutants contain amino acid changes in the alpha determinant of viral envelope proteins, the primary target of neutralizing antibodies. Our preliminary studies suggest that structural changes around the alpha determinant may impair virion secretion, but the possibility of the co-infecting wild-type virus or second-site mutations restoring virion secretion cannot be excluded. In the present study, we propose to analyze the virion secretion efficiencies of 21 alpha determinant mutants and 7 mutants associated with drug resistance. For mutants with defective or nearly defective virion secretion, which are nevertheless detectable in patient blood, we will determine whether the defect can be overcome by a small amount of wild-type envelope proteins or by introduction of an M133T mutation, which generates an extra N-linked glycosylation site. The M133T mutation can coevolve with and rescue the virion secretion defect of the classic G145R immune escape mutation. Furthermore, through a collaboration with Dr. Lok, we will directly verify whether the immune escape mutants found in patient blood are enveloped virus particles, or primarily as nonenveloped core particles. Virion secretion is part of viral life cycle critical for viral infectivity and transmission to new hosts. Therefore, establishing possible secretion defect of the immune escape mutants and whether the defect can be overcome by co-infecting wild-type virus or secondary mutations may help predict the future threat posed by immune escape mutants and design better containment strategies. If virion secretion is restored by co-infecting wild-type virus or a compensatory second-site mutation, their infectivity in the presence of neutralizing antibodies can be tested in the near future in a cell line infectible with HBV. This study will provide important information for the prevention and treatment of HBV infection and associated liver cancer. PUBLIC HEALTH RELEVANCE: The vaccines to prevent hepatitis B virus infection sometimes fail because escape mutants arise. We would like to determine the efficiency of such mutants to release virus from infected cells and the impact of co-infecting wild-type virus or additional mutations. The knowledge obtained will help adjust the vaccine strategy for better control of these mutants.

描述（由申请人提供）：全世界有近 4 亿人慢性感染乙型肝炎病毒 (HBV)，并面临肝硬化或肝癌的风险，需要进行肝移植。乙型肝炎病毒包膜蛋白免疫可预防乙型肝炎病毒感染，而乙型肝炎免疫球蛋白（HBIG）单独或与核苷类似物（如拉米夫定）一起使用，可降低移植肝的再感染率。然而，由于中和逃逸突变体的出现，通常与少量野生型病毒一起出现，疫苗接受者和肝移植接受者都可能发生突破性感染。这些突变体在病毒包膜蛋白的α决定簇中含有氨基酸变化，病毒包膜蛋白是中和抗体的主要靶标。我们的初步研究表明，α决定簇周围的结构变化可能会损害病毒体分泌，但不能排除共同感染野生型病毒或第二位点突变恢复病毒体分泌的可能性。在本研究中，我们建议分析 21 个 α 决定簇突变体和 7 个与耐药性相关的突变体的病毒颗粒分泌效率。对于病毒粒子分泌有缺陷或几乎有缺陷的突变体，但在患者血液中仍可检测到，我们将确定是否可以通过少量野生型包膜蛋白或通过引入 M133T 突变（产生额外的 N）来克服该缺陷。 -连接的糖基化位点。 M133T突变可以与经典G145R免疫逃逸突变的病毒体分泌缺陷共同进化并挽救。此外，通过与乐博士的合作，我们将直接验证患者血液中发现的免疫逃逸突变体是否是有包膜病毒颗粒，或者主要是无包膜核心颗粒。病毒颗粒分泌是病毒生命周期的一部分，对于病毒感染性和向新宿主的传播至关重要。因此，确定免疫逃逸突变体可能存在的分泌缺陷，以及是否可以通过共感染野生型病毒或二次突变来克服该缺陷，可能有助于预测免疫逃逸突变体未来带来的威胁，并设计更好的遏制策略。如果通过共同感染野生型病毒或补偿性第二位点突变来恢复病毒体分泌，那么在不久的将来可以在感染 HBV 的细胞系中测试它们在中和抗体存在下的感染性。该研究将为乙型肝炎病毒感染及相关肝癌的预防和治疗提供重要信息。公共卫生相关性：预防乙型肝炎病毒感染的疫苗有时会失败，因为出现逃逸突变体。我们希望确定此类突变体从受感染细胞中释放病毒的效率以及共同感染野生型病毒或其他突变的影响。获得的知识将有助于调整疫苗策略，以更好地控制这些突变体。