Tsubota A, Kumada H, Takaki K, Chayama K, Kobayashi M, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Murashima N, Ikeda K
Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.
J Med Virol. 1998 Dec;56(4):287-93. doi: 10.1002/(sici)1096-9071(199812)56:4<287::aid-jmv1>3.0.co;2-p.
To address the significance of mutations within the hepatitis B virus (HBV) core gene in chronic HBV infection, we followed prospectively HBe-antigen-positive asymptomatic healthy carriers, documented the onset of their disease based on serum alanine transaminase (ALT) concentrations, and analyzed sequentially serum samples from a quiescent phase through to an active phase of the chronic infection. In three female carriers, the first flare-up was documented during the follow-up period. Serial analysis by polymerase chain reaction, cloning, and sequencing of the HBV precore/core open reading frame genome demonstrated that clones with core gene deletions emerged during the quiescent phase and persisted subsequently during the active phase in two patients, who failed to seroconvert to anti-HBe and had persistently increased ALT levels despite interferon (IFN) therapy. The deletions were various, overlapping, and located in the mid-core region ranging from amino acid (aa) position 64 to 128. The remaining patient, who seroconverted with IFN therapy, did not have a core-gene-deletion HBV variant during follow-up, but had aa substitutions clustered in some restricted core regions. Two control asymptomatic carriers, who had no change in biochemical or virologic markers over a 15- to 19-year period, had no core-gene-deletion variants and few aa changes. These findings indicate that the mid-portion of the core gene is subject to deletion even during the quiescent phase. Thus, the immunologic interaction between the host and virus may occur insidiously, and the emergence of a core-gene-deletion HBV variant during the quiescent phase may be involved in the onset of hepatitis and the subsequent outcome of chronic infection.
为了探讨乙型肝炎病毒（HBV）核心基因内突变在慢性HBV感染中的意义，我们对HBe抗原阳性的无症状健康携带者进行了前瞻性随访，根据血清丙氨酸转氨酶（ALT）浓度记录其疾病发作情况，并对从慢性感染的静止期到活动期的血清样本进行了连续分析。在三名女性携带者中，随访期间记录到了首次病情发作。通过聚合酶链反应、克隆和对HBV前核心/核心开放阅读框基因组进行测序的系列分析表明，在两名患者的静止期出现了具有核心基因缺失的克隆，并在活动期持续存在，这两名患者未能血清学转换为抗-HBe，尽管接受了干扰素（IFN）治疗，但ALT水平持续升高。这些缺失各不相同且相互重叠，位于核心区域中部，范围从氨基酸（aa）位置64到128。另一名患者通过IFN治疗实现了血清学转换，随访期间没有核心基因缺失的HBV变异体，但在一些受限的核心区域有aa替代。两名无症状对照携带者在15至19年期间生化或病毒学标志物没有变化，没有核心基因缺失变异体，aa变化也很少。这些发现表明，即使在静止期，核心基因的中部也会发生缺失。因此，宿主与病毒之间的免疫相互作用可能在不知不觉中发生，静止期核心基因缺失的HBV变异体的出现可能与肝炎的发作及慢性感染的后续结果有关。
