Hepatitis B virus immune escape mutants

乙型肝炎病毒免疫逃逸突变体

• 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
• 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

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）：全世界近4亿人患有丙型肝炎病毒（HBV），并且有肝硬化或肝癌的风险，这需要肝移植。用HBV包膜蛋白免疫可防止HBV感染，丙型肝炎免疫球蛋白（HBIG）单独或与诸如lamivudine之类的核苷类似物一起降低了移植肝的感染率。但是，由于中和逃避突变体的出现，疫苗接收者和肝植物接收者可能会发生突破感染，通常与少量的野生型病毒一起。这种突变体在病毒包膜蛋白的α决定因素（中和抗体的主要靶标）中包含氨基酸变化。我们的初步研究表明，α决定因素周围的结构变化可能会损害病毒率的分泌，但是不能排除恢复病毒体分泌的野生型病毒或第二位点突变的可能性。在本研究中，我们建议分析21个αα行决定因子突变体和7种与耐药性相关的突变体的病毒体分泌效率。对于在患者血液中仍可检测到的具有缺陷或几乎有缺陷的病毒体分泌的突变体，我们将确定是否可以通过少量的野生型包膜蛋白或引入M133T突变来克服缺陷，从而产生额外的N-连接糖基化位点。 M133T突变可以与经典G145R免疫逃逸突变的病毒体分泌缺陷进行并挽救。此外，通过与Lok博士的合作，我们将直接验证患者血液中发现的免疫逃生突变体是包膜的病毒颗粒，还是主要是未开发的核心颗粒。病毒分泌是病毒感染和向新宿主传播至关重要的病毒生命周期的一部分。因此，建立免疫逃逸突变体的可能分泌缺陷，以及是否可以通过共同感染野生型病毒或二次突变来克服缺陷可能有助于预测免疫逃生突变体和设计更好的遏制策略所构成的未来威胁。如果通过共同感染野生型病毒或补偿性第二站点突​​变来恢复病毒体的分泌，则可以在不久的将来在具有HBV感染的细胞系中测试其在中和抗体存在下的感染性。这项研究将为预防和治疗HBV感染和相关肝癌提供重要信息。 公共卫生相关性：防止乙型肝炎病毒感染的疫苗有时会失败，因为逃生突变体发生了。我们想确定此类突变体从感染细胞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。