Regulation of the life cycle of HDV by the drug resistance mutations of HBV

乙型肝炎病毒耐药突变对丁型肝炎病毒生命周期的调控

• 批准号: 10285584
• 负责人: Severin O Gudima
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285584
• 关键词: Address; Affect; Amino Acids; Antibodies; Area; Binding; Binding Sites; Biological Assay; Cells; Chronic; Chronic Hepatitis D; Cirrhosis; Clinic; Complex; Data; Drug resistance; FDA approved; Genome; Genotype; HBV Genotype; HepG2; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B virus Pol Protein; Hepatitis D; Hepatitis Delta Virus; Hepatitis delta Antigens; Hepatocyte; Human; Immune response; Immunofluorescence Immunologic; Immunoglobulins; In Vitro; Individual; Lamivudine; Lead; Life Cycle Stages; Liver; Liver diseases; Location; Maintenance; Mediating; Mutate; Mutation; Open Reading Frames; Outcome; Pathogenesis; Pharmaceutical Preparations; Plasma; Plasmids; Polymerase Gene; Primary Infection; Primary carcinoma of the liver cells; Property; Regulation; Research; Risk; Role; Site; Surface Antigens; Telbivudine; Tenofovir; Time; Transfection; Transmembrane Domain; Ursidae Family; Variant; Viral; Viral Genome; Viral Pathogenesis; Viral Proteins; Virion; Virus; Virus Assembly; Virus Diseases; Virus Receptors; Work; adefovir; anti-hepatitis B; base; chronic infection; entecavir; env Gene Products; human pathogen; mutant; resistance mechanism; resistance mutation; superinfection; vector; viral RNA; virus host interaction

Abstract Hepatitis delta virus (HDV) is a natural sub-viral agent of hepatitis B virus (HBV), which uses HBV envelope proteins (i.e., surface antigen, HBsAg) to form the virions and infect hepatocytes via HBV receptor. Out of 257 million people chronically infected with HBV worldwide about 20 million are also chronically infected with HDV. HDV remains a significant human pathogen. HDV infection causes additional liver pathogenesis, and can accelerate liver disease, can cause more rapid and frequent cirrhosis, and can elevate risk of hepatocellular carcinoma (HCC). Anti-HBV drugs do not block HDV infection. No drugs directly targeting HDV exist in clinic. Mechanism of HDV infection is far from being fully understood, which affects the treatment options. HDV-HBV interactions are complex and under-studied. The regulation of HDV life cycle by the drug-resistant mutants of HBV remains under-studied as well. Therefore, this proposal will examine how the drug resistance mutations in HBV genome selected during the treatment with FDA-approved anti-HBV drugs, lamivudine, adefovir, telbivudine, entecavir or tenofovir, can influence HDV infection. The primary mutations that occur in the open reading frame (ORF) of HBV polymerase can lead to the corresponding drug resistance mutations (DRMs) in the overlapping ORF for HBsAg. DRMs were found in the large cytosolic loop (LCL), major antigenic loop (MAL), HDV-binding site (HDV-BS), and second, third and fourth transmembrane domains (TMDs II-IV) of HBsAg. MAL is critical for infectivity of HBV and HDV, and it is a major regulator of the antigenicity of HBV and HDV virions (i.e., recognition of the virions by anti-HBsAg antibodies). HDV-BS mediates HBsAg interactions with the large delta antigen during HDV assembly. Thus, DRMs are expected to regulate the mechanisms of the HDV assembly and infectivity, and could affect HDV-host interactions. Our previous work suggested that the infectivity of the virions, virus spread and super-infection (i) could determine if initial HDV infection will be cleared or it will become persistent (i.e., chronic) infection, and (ii) also could be critical for the maintenance of the chronic state of HDV infection. We also found that amino acids of HBsAg that regulate the assembly of HDV virions can influence their infectivity as well. Furthermore, the efficiency of HDV assembly can greatly affect HDV spread and super-infection. Current understanding of the mechanisms how DRMs regulate the assembly and infectivity of HDV, and recognition of HDV by anti-HBsAg antibodies is very limited. Therefore, Aim 1 will analyze in detail how HBsAg bearing DRMs can regulate the assembly of HDV and affect the recognition of HDV virions by anti-HBsAg antibodies of the hepatitis B immune globulin (HBIg). Furthermore, Aim 2 will examine the effects of DRMs on the infectivity of HDV virions. Overall, the proposal will considerably advance our understanding of the mechanisms of how the drug-resistant mutants of HBV influence the HBV- HDV interactions, and regulate the assembly, infectivity and antigenicity of HDV virions, which is expected to influence the outcomes of HDV infection and the extent of HDV pathogenesis.

抽象的 肝炎三角洲病毒（HDV）是使用HBV包膜的丙型肝炎病毒（HBV）的天然次病药物 蛋白质（即表面抗原，Hbsag）通过HBV受体形成病毒体并感染肝细胞。在257中 百万长期感染HBV的人在全球范围内感染了大约2000万人，还感染了HDV。 HDV仍然是人类病原体。 HDV感染会引起其他肝脏发病机理，并且可以 加速肝病，可能引起更快，更频繁的肝硬化，并且可以提高肝细胞的风险 癌（HCC）。抗HBV药物不会阻止HDV感染。在诊所中，没有直接靶向HDV的药物。 HDV感染的机制远非充分理解，这会影响治疗方案。 HDV-HBV 相互作用很复杂且研究不足。通过耐药突变体对HDV生命周期的调节 HBV的研究也不足。因此，该提案将研究如何中的耐药性突变 在用FDA批准的抗HBV药物治疗期间选择的HBV基因组，lamivudine，adefovir， 雌激素，Entecavir或Tenofovir会影响HDV感染。公开发生的主要突变 HBV聚合酶的阅读框（ORF）可以导致相应的耐药性突变（DRM） HBSAG的重叠ORF。在大胞质环（LCL），主要抗原环中发现了DRM （MAL），HDV结合位点（HDV-BS）以及第二，第三和第四跨膜域（TMDS II-IV） hbsag。 MAL对于HBV和HDV的感染性至关重要，它是HBV抗原性和 HDV病毒体（即，通过抗HBSAG抗体对病毒体的识别）。 HDV-BS介导HBSAG相互作用 在HDV组件期间，具有大三角洲抗原。因此，预计DRM将调节 HDV组装和感染性，可能会影响HDV-host相互作用。我们以前的工作表明 病毒体，病毒扩散和超级感染的感染性（i）可以确定初始HDV感染是否会 清除或它将变得持久（即慢性）感染，（ii）也可能对维持至关重要 HDV感染的慢性状态。我们还发现，调节组装的HBSAG的氨基酸 HDV病毒体也会影响其感染力。此外，HDV组装的效率大大可以 影响HDV扩散和超级感染。当前对机制的理解如何调节 HDV的组装和感染性，以及抗HBSAG抗体对HDV的识别非常有限。所以， AIM 1将详细分析HBSAG轴承DRM如何调节HDV的组装并影响 通过丙型肝炎免疫球蛋白（HBIG）的抗HBSAG抗体对HDV病毒体的识别。此外， AIM 2将检查DRM对HDV病毒体感染性的影响。总体而言，该提议将大大 促进我们对HBV耐药突变体如何影响HBV的机制的理解 HDV相互作用，并调节HDV病毒体的组装，感染性和抗原性，预计将 影响HDV感染的结局和HDV发病机理的程度。