Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Department of Microbiology and Immunology, Faculty of Medicine, Tanta University, Egypt, Egypt.
Adv Exp Med Biol. 2020;1179:39-69. doi: 10.1007/978-981-13-9151-4_3.
Hepatitis B virus (HBV) is a major human pathogen lacking a reliable curative therapy. Current therapeutics target the viral reverse transcriptase/DNA polymerase to inhibit viral replication but generally fail to resolve chronic HBV infections. Due to the limited coding potential of the HBV genome, alternative approaches for the treatment of chronic infections are desperately needed. An alternative approach to the development of antiviral therapeutics is to target cellular gene products that are critical to the viral life cycle. As transcription of the viral genome is an essential step in the viral life cycle, the selective inhibition of viral RNA synthesis is a possible approach for the development of additional therapeutic modalities that might be used in combination with currently available therapies. To address this possibility, a molecular understanding of the relationship between viral transcription and replication is required. The first step is to identify the transcription factors that are the most critical in controlling the levels of HBV RNA synthesis and to determine their in vivo role in viral biosynthesis. Mapping studies in cell culture utilizing reporter gene constructs permitted the identification of both ubiquitous and liver-enriched transcription factors capable of modulating transcription from the four HBV promoters. However, it was challenging to determine their relative importance for viral biosynthesis in the available human hepatoma replication systems. This technical limitation was addressed, in part, by the development of non-hepatoma HBV replication systems where viral biosynthesis was dependent on complementation with exogenously expressed transcription factors. These systems revealed the importance of specific nuclear receptors and hepatocyte nuclear factor 3 (HNF3)/forkhead box A (FoxA) transcription factors for HBV biosynthesis. Furthermore, using the HBV transgenic mouse model of chronic viral infection, the importance of various nuclear receptors and FoxA isoforms could be established in vivo. The availability of this combination of systems now permits a rational approach toward the development of selective host transcription factor inhibitors. This might permit the development of a new class of therapeutics to aid in the treatment and resolution of chronic HBV infections, which currently affects approximately 1 in 30 individuals worldwide and kills up to a million people annually.
乙型肝炎病毒（HBV）是一种主要的人类病原体，缺乏可靠的治愈疗法。目前的治疗方法针对病毒的逆转录酶/DNA 聚合酶，以抑制病毒复制，但通常无法解决慢性 HBV 感染。由于 HBV 基因组的编码潜力有限，因此迫切需要寻找治疗慢性感染的替代方法。开发抗病毒治疗的替代方法是针对对病毒生命周期至关重要的细胞基因产物。由于病毒基因组的转录是病毒生命周期中的一个关键步骤，因此选择性抑制病毒 RNA 合成是开发可能与现有治疗方法联合使用的额外治疗方法的一种可能方法。为了解决这个问题，需要从分子水平上了解病毒转录和复制之间的关系。第一步是确定对控制 HBV RNA 合成水平最关键的转录因子，并确定它们在病毒生物合成中的体内作用。利用报告基因构建体在细胞培养中的作图研究，鉴定了能够调节四个 HBV 启动子转录的普遍存在和肝富集转录因子。然而，在现有的人类肝癌复制系统中，确定它们对病毒生物合成的相对重要性具有挑战性。部分解决了这一技术限制，开发了非肝癌 HBV 复制系统，其中病毒生物合成依赖于外源性表达的转录因子的互补作用。这些系统揭示了特定核受体和肝细胞核因子 3（HNF3）/叉头框 A（FoxA）转录因子对 HBV 生物合成的重要性。此外，利用慢性病毒感染的 HBV 转基因小鼠模型，可以在体内确定各种核受体和 FoxA 同工型的重要性。这种组合系统的可用性现在可以实现针对选择性宿主转录因子抑制剂的合理方法。这可能会开发出一类新的治疗药物，以帮助治疗和解决慢性 HBV 感染，目前全球约有 1/30 的人受到感染，每年多达 100 万人因此死亡。
