未经证实:HBV表现出广泛的遗传多样性,至少有9个基因型(GT),在患病率方面有所不同,地理分布,自然史,疾病进展,和治疗结果。然而,HBV复制能力的差异,基因表达,不同GTs的感染能力仍未完全理解。在这里,我们的目的是使用新构建的覆盖主要HBVGTs的感染性克隆来研究这些关键方面。
未经证实:在细胞系中分析了覆盖HBVGTsA-E的感染性克隆的复制能力,原代肝细胞和人源化小鼠。在流体动力学注射的小鼠中表征由不同HBVGT诱导的宿主反应和组织病理学。恩替卡韦和各种HBV衣壳抑制剂的治疗反应的差异也在不同的遗传定义的GTs定量。
未经证实:患者来源的HBV感染性克隆在体外和体内都强劲复制。GTsA和D诱导更明显的肝内和促炎细胞因子反应,与更快的病毒清除相关。值得注意的是,转染到HepG2细胞后,所有5个HBV克隆稳健产生的病毒颗粒,这些颗粒在HepG2-NTCP细胞中具有感染性,原代人肝细胞和人嵌合小鼠。值得注意的是,GTD病毒表现出比GTsA更高的感染性,B,C和E在体外,尽管它与人肝嵌合小鼠体内的GTA和B相当。HBV衣壳抑制剂更容易抑制HBVGTsA,B,D和E比C.
UNASSIGNED:这里描述的感染性克隆作为遗传工具具有广泛的实用性,可以机械地剖析抗病毒免疫和发病机理的基因型间差异,并有助于HBV药物开发和筛选。
未经评估:乙型肝炎病毒(HBV)是人类发病率和死亡率的主要因素。HBV可以分为许多基因型,根据他们的特定基因组成,其中9个是众所周知的。我们分离并克隆了其中5种基因型的基因组,并利用它们为这种临床重要病毒的未来研究创造了有价值的工具。
UNASSIGNED: HBV exhibits wide genetic diversity with at least 9 genotypes (GTs), which differ in terms of prevalence, geographic distribution, natural history, disease progression, and treatment outcome. However, differences in HBV replicative capacity, gene expression, and infective capability across different GTs remain incompletely understood. Herein, we aimed to study these crucial aspects using newly constructed infectious clones covering the major HBV GTs.
UNASSIGNED: The replicative capacity of infectious clones covering HBV GTs A-E was analyzed in cell lines, primary hepatocytes and humanized mice. Host responses and histopathology induced by the different HBV GTs were characterized in hydrodynamically injected mice. Differences in treatment responses to entecavir and various HBV capsid inhibitors were also quantified across the different genetically defined GTs.
UNASSIGNED: Patient-derived HBV infectious clones replicated robustly both in vitro and in vivo. GTs A and D induce more pronounced intrahepatic and proinflammatory cytokine responses which correlated with faster viral clearance. Notably, all 5 HBV clones robustly produced viral particles following transfection into HepG2 cells, and these particles were infectious in HepG2-NTCP cells, primary human hepatocytes and human chimeric mice. Notably, GT D virus exhibited higher infectivity than GTs A, B, C and E in vitro, although it was comparable to GT A and B in the human liver chimeric mice in vivo. HBV capsid inhibitors were more readily capable of suppressing HBV GTs A, B, D and E than C.
UNASSIGNED: The infectious clones described here have broad utility as genetic tools that can mechanistically dissect intergenotypic differences in antiviral immunity and pathogenesis and aid in HBV drug development and screening.
UNASSIGNED: The hepatitis B virus (HBV) is a major contributor to human morbidity and mortality. HBV can be categorized into a number of genotypes, based on their specific genetic make-up, of which 9 are well known. We isolated and cloned the genomes of 5 of these genotypes and used them to create valuable tools for future research on this clinically important virus.