Okamoto H, Yotsumoto S, Akahane Y, Yamanaka T, Miyazaki Y, Sugai Y, Tsuda F, Tanaka T, Miyakawa Y, Mayumi M
Immunology Division, Jichi Medical School, Japan.
J Virol. 1990 Mar;64(3):1298-303. doi: 10.1128/JVI.64.3.1298-1303.1990.
The C gene of hepatitis B virus (HBV) codes for a nucleocapsid protein made of 183 amino acid residues and is preceded in phase by the precore (pre-C) region, encoding 29 residues. The pre-C-region product is required for the synthesis and secretion of hepatitis B e antigen (HBeAg), which is made of the C-terminal 10 amino acid residues of the pre-C-region product and the N-terminal 149 residues of the C-gene product. HBV mutants with pre-C-region defects prevailed in the circulation of three asymptomatic carriers as they seroconverted from HBeAg to the corresponding antibody (anti-HBe), and these mutants finally replaced nondefective HBV. HBV DNA clones were propagated from sera of an additional 15 carriers with anti-HBe and sequenced for the pre-C region. Essentially all HBV DNA clones (56 of 57 [98%]) revealed mutations that prohibited the translation of a functional pre-C-region product. A point mutation from G to A at nucleotide 83, converting Trp-28 (TGG) to a stop codon (TAG), was by far the commonest and was observed in HBV DNA clones from 16 (89%) of 18 carriers seropositive for anti-HBe. In addition, there were point mutations involving ATG codon to abort the translation initiation of the pre-C region, as well as deletion and insertion to induce frameshifts. Such mutations leading to pre-C-region defects were rarely observed in persistently infected individuals positive for HBeAg or in patients with type B acute hepatitis after they had seroconverted to anti-HBe. These results would indicate a selection of pre-C-defective mutants in persistently infected hosts, along with seroconversion to anti-HBe, by immune elimination of hepatocytes harboring nondefective HBV with the expression of HBeAg.
乙型肝炎病毒（HBV）的C基因编码一种由183个氨基酸残基组成的核衣壳蛋白，其上游相位是前核心（pre-C）区，编码29个残基。前核心区产物是乙型肝炎e抗原（HBeAg）合成和分泌所必需的，HBeAg由前核心区产物的C末端10个氨基酸残基和C基因产物的N末端149个残基组成。在前核心区存在缺陷的HBV突变体在三名无症状携带者从HBeAg血清学转换为相应抗体（抗-HBe）时在其循环中占主导地位，并且这些突变体最终取代了无缺陷的HBV。从另外15名抗-HBe携带者的血清中扩增HBV DNA克隆，并对前核心区进行测序。基本上所有的HBV DNA克隆（57个中的56个[98%]）都显示出突变，这些突变阻止了功能性前核心区产物的翻译。核苷酸83处从G到A的点突变，将Trp-28（TGG）转换为终止密码子（TAG），是迄今为止最常见的，在18名抗-HBe血清阳性携带者中的16名（89%）的HBV DNA克隆中观察到。此外，还有涉及ATG密码子的点突变，以中止前核心区的翻译起始，以及导致移码的缺失和插入。在HBeAg阳性的持续感染个体或B型急性肝炎患者血清学转换为抗-HBe后，很少观察到导致前核心区缺陷的此类突变。这些结果表明，在持续感染的宿主中，随着血清学转换为抗-HBe，通过免疫清除携带表达HBeAg的无缺陷HBV的肝细胞，选择了前核心缺陷突变体。
