HBV genotypes A1 and A2 have distinct replication phenotypes due to polymorphisms in the HBV X gene

HBV is a leading cause of liver disease worldwide. HBV genotypes have distinct geographical distributions, routes of transmission, virological features and clinical characteristics. HBV subtypes A1 and A2, despite being classified within one genotype, appear to have distinct virologic and clinical features. Whether such differences among the diverse HBV genotypes resulting from the virus or host has not been established mostly because of limitations in cell culture tools and models. Here we establish and apply infectious in vitro and in vivo systems to study the virological behaviors and treatment responses of HBV A1 and A2. The surprising and intriguing finding of subtype A2 having a higher replication phenotype because of polymorphisms in the <i>HBx</i> gene provides the first indication that sequence variations, specifically in <i>HBx</i><i> </i>gene here and possibly elsewhere on the genome, may underpin the diverse clinical phenotypes of HBV infections. This study underscores the value of this platform in investigating HBV biology and the need to study genotype-phenotype differences among the diverse HBV genotypes that may offer unique insight into functions of viral proteins and regulatory elements.

乙型肝炎病毒（hepatitis B virus, HBV）是全球范围内引发肝脏疾病的首要病因。HBV基因型具有差异化的地理分布特征、传播途径、病毒学特性与临床表型。尽管HBV亚型A1与A2同属一个基因型，但二者却呈现出显著不同的病毒学与临床特征。目前，由于细胞培养工具及模型存在局限性，绝大多数情况下尚未明确：这种不同HBV基因型间的差异究竟源于病毒本身还是宿主因素。本研究建立并应用了体外（in vitro）与体内（in vivo）感染研究体系，以探究HBV A1和A2亚型的病毒学行为及治疗应答情况。本研究中一项令人意外且引人关注的发现为：因HBx基因存在多态性，A2亚型展现出更高的复制表型——这首次提示，序列变异（尤其是本研究中的HBx基因以及基因组其他潜在区域）或许是HBV感染多样化临床表型的核心成因。本研究凸显了该研究平台在HBV生物学特性探究中的应用价值，同时也强调了针对不同HBV基因型间基因型-表型差异开展研究的必要性，此类研究或可为病毒蛋白与调控元件的功能解析提供独特视角。