PATHOGENESIS, CHRONICITY, AND MUTATIONS OF HEPATITIS B

描述：慢性感染人类乙肝病毒(乙肝病毒)导致 肝损伤、肝硬变和肝癌。申请者的目标是 阐明其致病、慢性化和清除的分子基础 乙肝病毒感染。尽管慢性病被归因于宿主因素， 例如免疫反应，病毒本身的因素在很大程度上仍然存在 未经调查。申请人的初步结果表明，在慢性疾病中 携带者和肝癌患者乙肝病毒获得性突变可能导致抗原性 导致免疫系统逃逸的变化。他们提议测试 更直接、更明确的假设是某些物质的积累 病毒变异对致病性乙肝病毒在其感染过程中的持久性至关重要 与主持人长期互动。免疫病理相互作用 将通过以下途径研究某些乙肝核心抗原突变株与宿主之间的关系 多肽-主要组织相容性复合体(多肽-MHC)结合试验， 抗原处理和T细胞受体识别。具体地说，三个 目标被提出：目标1)检验某些核心抗原 突变会影响MHC与多肽的结合；目的2)检验假设 免疫逃逸可能导致异常的乙肝病毒核心抗原处理 突变体；目的3)检验某些核心抗原突变 影响TCR多肽-MHC识别。这最后一个目标可以扩展到 包括TCR拮抗型或激动型突变核心的检查 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.