PATHOGENESIS, CHRONICITY, AND MUTATIONS OF HEPATITIS B

描述：慢性感染人B肝炎病毒（HBV）导致 肝损伤、肝硬化和肝癌。 申请人的目标是 阐明致病性，慢性化和清除的分子基础， HBV感染 虽然慢性化被归因于宿主因素， 如免疫反应，病毒因素本身仍然主要是 未经调查 申请人的初步结果表明，在慢性 携带者和肝癌患者HBV获得性突变可能导致抗原性 导致免疫系统逃逸的变化。 他们打算测试 更直接和明确的假设，积累的某些 病毒突变是至关重要的致病性HBV的持久性， 与宿主的长期互动。 免疫病理学相互作用 将通过以下方式研究某些HBV核心抗原突变体与宿主之间的关系 肽-主要组织相容性复合体（肽-MHC）结合的测定， 抗原加工和T细胞受体识别。 具体来说，三 目的：1）验证某些核心抗原 突变影响MHC-肽结合;目的2）检验以下假设： HBV核心抗原的异常加工可能是免疫逃逸所致 目的3）检验某些核心抗原突变 影响TCR肽-MHC识别。 这最后一个目标可以扩大到 包括检查TCR拮抗性或激动性突变核心 抗原

DESCRIPTION: Chronic infection with human hepatitis B virus (HBV) leads to liver damage, cirrhosis and liver cancer. The applicant's goal is to elucidate the molecular basis of pathogenicity, chronicity, and clearance of HBV infection. Although chronicity has been attributed to host factors, such as the immune response, viral factors per se have remained largely uninvestigated. The applicant's preliminary results suggest that in chronic carriers and hepatoma patients HBV-acquired mutations may cause antigenic changes that lead to escape from the immune system. They propose to test more directly and definitively the hypothesis that accumulation of certain viral mutations is crucial for the persistence of pathogenic HBV during its long term interaction with the host. The immunopathological interactions between certain HBV core antigen mutants and the host will be studied via assays for peptide-major histocompatibility complex (peptide-MHC) binding, antigen processing and T cell receptor recognition. Specifically, three aims are proposed: Aim 1) to test the hypothesis that certain core antigen mutations affect MHC-peptide binding; Aim 2) to test the hypothesis that aberrant HBV core antigen processing could result from immune escape mutants; Aim 3) to test the hypothesis that certain core antigen mutations affect TCR peptide-MHC recognition. This last aim may be expanded to include the examination of TCR-antagonistic or agonistic mutant core antigens.