Molecular Mechanisms Of Hepatitis B Viral Pathogenesis And Persistence

目前的抗病毒药物可以控制但不能消除乙型肝炎病毒（HBV），因为HBV建立了稳定的核cccDNA。干扰素治疗可以清除HBV，但受到全身副作用的限制。已知IFN-&#945；对HBV发挥转录、转录后和表观遗传抗病毒作用。我们研究了干扰素如何在不引起肝毒性的情况下诱导核病毒DNA的特异性降解，并提出淋巴毒素受体激活作为一种治疗替代方案。干扰素-和淋巴毒素-受体激活分别在hbv感染细胞、原代肝细胞和人肝穿刺活检中上调APOBEC3A和3B胞苷脱氨酶。hbv核心蛋白介导与核cccDNA的相互作用，导致胞苷脱胺，无尿嘧啶/无嘧啶位点形成，最终cccDNA降解，阻止hbv再激活。另一方面，基因组DNA没有受到影响。我们的数据表明，cccDNA降解是可能的，并且可以被诱导而对感染的宿主细胞没有副作用。一项重要的任务将是测试核苷类似物与新型抗病毒策略（如lt - R激动剂或过继t细胞治疗）的组合，以激活A3A或A3B来治愈乙肝。因此，通过淋巴毒素受体激活诱导核脱氨酶，可以开发新的治疗方法，与现有的抗病毒药物联合治疗乙肝。

Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-α treatment can clear HBV but is limited by systemic side effects. IFN-α is known to exert transcriptional, post-transcriptional and epigenetic antiviral effects on HBV. We study how interferon-α can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β-receptor activation as a therapeutic alternative. Interferon-α and lymphotoxin-β-receptor activation up-regulated APOBEC3A and 3B cytidine-deaminases, respectively, in HBV-infected cells, primary hepatocytes and human liver-needle biopsies. HBV-core protein mediated the interaction with nuclear cccDNA resulting in cytidine-deamination, apurinic/apyrimidinic site formation and finally cccDNA degradation that prevented HBV-reactivation. On the other hand, genomic DNA was not affected. Our data indicate that cccDNA degradation is possible and can be induced without side-effects on the infected host cell. An important task will be testing of combinations of nucleos(t)ide analogues with novel anti-viral strategies (e.g. LTβR agonists or adoptive T-cell therapy) to activate A3A or A3B to cure hepatitis B. Thus, inducing nuclear deaminases e.g., by lymphotoxin-β-receptor activation allows development of new therapeutics that, combined with existing antivirals may cure hepatitis B.