Casey J L, Gerin J L
Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Maryland 20852, USA.
J Virol. 1998 Apr;72(4):2806-14. doi: 10.1128/JVI.72.4.2806-2814.1998.
Characterizations of genetic variations among hepatitis delta virus (HDV) isolates have focused principally on phylogenetic analysis of sequences, which vary by 30 to 40% among three genotypes and about 10 to 15% among isolates of the same genotype. The significance of the sequence differences has been unclear but could be responsible for pathogenic variations associated with the different genotypes. Studies of the mechanisms of HDV replication have been limited to cDNA clones from HDV genotype I, which is the most common. To perform a comparative analysis of HDV RNA replication in genotypes I and III, we have obtained a full-length cDNA clone from an HDV genotype III isolate. In transfected Huh-7 cells, the functional roles of the two forms of the viral protein, hepatitis delta antigen (HDAg), in HDV RNA replication are similar for both genotypes I and III; the short form is required for RNA replication, while the long form inhibits replication. For both genotypes, HDAg was able to support replication of RNAs of the same genotype that were mutated so as to be defective for HDAg production. Surprisingly, however, neither genotype I nor genotype III HDAg was able to support replication of such mutated RNAs of the other genotype. The inability of genotype III HDAg to support replication of genotype I RNA could have been due to a weak interaction between the RNA and HDAg. The clear genotype-specific activity of HDAg in supporting HDV RNA replication confirms the original categorization of HDV sequences in three genotypes and further suggests that these should be referred to as types (i.e., HDV-I and HDV-III) rather than genotypes.
丁型肝炎病毒（HDV）分离株之间遗传变异的特征主要集中在序列的系统发育分析上，三种基因型之间的序列差异为30%至40%，同一基因型的分离株之间的差异约为10%至15%。序列差异的意义尚不清楚，但可能与不同基因型相关的致病变异有关。HDV复制机制的研究仅限于最常见的HDV基因型I的cDNA克隆。为了对HDV基因型I和III中的RNA复制进行比较分析，我们从一株HDV基因型III分离株中获得了一个全长cDNA克隆。在转染的Huh-7细胞中，两种形式的病毒蛋白，即丁型肝炎抗原（HDAg），在HDV RNA复制中的功能作用在基因型I和III中相似；短形式是RNA复制所必需的，而长形式则抑制复制。对于这两种基因型，HDAg能够支持因HDAg产生缺陷而发生突变的同基因型RNA的复制。然而，令人惊讶的是，基因型I和基因型III的HDAg都不能支持另一种基因型的这种突变RNA的复制。基因型III的HDAg不能支持基因型I RNA的复制可能是由于RNA与HDAg之间的相互作用较弱。HDAg在支持HDV RNA复制方面明显的基因型特异性活性证实了HDV序列最初分为三种基因型的分类，并进一步表明这些应称为类型（即HDV-I和HDV-III）而不是基因型。
