The geographic distribution of hepatitis B virus (HBV) genotypes in Japan and its clinical relevance are poorly understood. We studied 731 Japanese patients with chronic HBV infection. HBV genotype was determined by the restriction fragment length polymorphism (RFLP) method after polymerase chain reaction (PCR). Of the 720 patients with positive PCR, 12 (1.7%) were HBV genotype A, 88 (12.2%) were genotype B, 610 (84.7%) were genotype C, 3 (0.4%) were genotype D, and 7 (1.0%) were of mixed genotype. Over 94% of patients on the Japanese mainland had genotype C, while 60% of the patients on Okinawa, the most southern islands, and 22.9% in the Tohoku area, the northern part of the mainland, harbored genotype B. Compared with genotype C patients, genotype B patients were older (53.6 to 42.2 years; P < .01), had a lower rate of positive hepatitis B e antigen (HBeAg) (18.4% to 50.6%; P < .01), and a lower level of serum HBV DNA (5.02 to 5.87 log genome equivalents (LGE)/mL; P < .01). The mean age of the genotype B patients with hepatocellular carcinoma was 70.1 ؎ 9.2 years, compared with 55.2 ؎ 9.7 of genotype C patients (P < .01). These results indicate that genotypes C and B are predominant in Japan, and there are significant differences in geographic distribution and clinical characteristics among the patients with the different genotypes. (HEPATOLOGY 2001;34:590-594.)Hepatitis B virus (HBV), a member of hepadnaviridae, is a circular double-stranded DNA virus, and is one of the major causative agents of chronic liver diseases, especially in Asian and African countries. HBV had formerly been classified into 4 major subtypes, which were defined serologically. 1 However, the classification of HBV by serologic subtype is not rational because of a change of subtype resulting from one point mutation at the S gene. 2 Thus, according to the molecular evolutionary analysis of the genomic DNA sequence, HBV strains isolated in various countries are classified into 7 genotypes: genotypes A to G. 3

No abstract

Using human immune globulins made from antihepatitis C virus (HCV)-positive plasma, we recently identified two antibody epitopes in the E2 protein at residues 412-426 (epitope I) and 434 -446 (epitope II). Whereas epitope I is highly conserved among genotypes, epitope II varies. We discovered that epitope I was implicated in HCV neutralization whereas the binding of nonneutralizing antibody to epitope II disrupted virus neutralization mediated by antibody binding at epitope I. These findings suggested that, if this interfering mechanism operates in vivo during HCV infection, a neutralizing antibody against epitope I can be restrained by an interfering antibody, which may account for the persistence of HCV even in the presence of an abundance of neutralizing antibodies. We tested this hypothesis by affinity depletion and peptide-blocking of epitope-II-specific antibodies in plasma of a chronically HCV-infected patient and recombinant E1E2 vaccinated chimpanzees. We demonstrate that, by removing the restraints imposed by the interfering antibodies to epitope-II, neutralizing activity can be revealed in plasma that previously failed to neutralize viral stock in cell culture. Further, cross-genotype neutralization could be generated from monospecific plasma. Our studies contribute to understanding the mechanisms of antibody-mediated neutralization and interference and provide a practical approach to the development of more potent and broadly reactive hepatitis C immune globulins. M ost hepatitis C virus (HCV)-infected patients fail to clear the virus and, despite the presence of neutralizing antibodies (NAbs), develop chronic infections. These chronically HCV-infected patients are at risk of developing cirrhosis and liver cancer (1, 2). Although current standard treatment with pegylated IFN and ribavirin results in cures in as many as 50% of patients, neither antibody-based prophylaxis nor an effective vaccine is available.The mechanism by which HCV persists in the presence of NAbs is unknown. Heterogeneity, a prominent feature of HCV, has been considered important in immune escape. Previously we identified an antigenic region in the E2 envelope glycoprotein of hepatitis C virus that contains two important epitopes, i.e., epitope I and epitope II. Epitope I has been recognized by us and others as an important neutralization site (3, 4). We showed that antibody to epitope II interfered with antibody to epitope I, inhibiting neutralization of the virus (4). In this study, we have further characterized these epitopes and identified the amino acid residues in epitope I important for antibody binding. By absorbing out antibody to epitope II in plasma from a chronically infected HCV patient, we show that neutralizing activity is not only enhanced but also broadened to include additional genotypes of the virus. Furthermore, by using plasma from 2 chimpanzees that had been vaccinated with recombinant E1 and E2 envelope glycoproteins of a genotype 1a HCV, we demonstrate that a monotypic immune response contained cross-neutra...

No abstract