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Sugauchi F.,Nagoya City Koseiin Medcial Welfare Center | Tanaka Y.,Nagoya City University | Kusumoto S.,Nagoya City University | Matsuura K.,Nagoya City University | And 4 more authors.
Journal of Medical Virology | Year: 2011

The virological characteristics of hepatitis B virus (HBV) implicated in the reactivation of occult hepatitis B in patients who have received hematopoietic stem-cell transplantation or chemotherapy for the hematological malignancy are not well defined. Twenty-eight HBsAg-negative patients who received hematopoietic stem-cell transplantation and 138 HBsAg-negative patients treated for malignant lymphoma with chemotherapy including rituximab were enrolled. Three of the 28 patients (10.7%) received hematopoietic stem-cell transplantation and one of the 138 (0.72%) patients treated for malignant lymphoma with chemotherapy developed de novo HBV hepatitis. Anti-HBc was detected in four and anti-HBs in two patients. Genotype Bj was detected in two and C in two of they all possessed wild-type sequences in the core promoter region. A precore stop mutation (A1896) was detected in a patient with genotype Bj who developed fulminant hepatic failure. HBV DNA was detected in pretreatment HBsAg-negative samples in two of four patients, and the HBV genome sequence identified from sera before chemotherapy and at the time of de novo HBV hepatitis showed 100% homology. In an in vitro replication model, genotype Bj with the A1896 clone obtained from a fulminant case had a replication level much higher than clones obtained from de novo hepatitis B patients with genotype Bj or C with G1896. In conclusion, this is the first report demonstrating de novo hepatitis B from the reactivation of occult HBV infection confirmed by molecular evolutional analysis. The fulminant outcome of HBV reactivation can be associated with genotype Bj exhibiting high replication due to the A1896 mutation. J. Med. Virol. 83:412-418, 2011. © 2011 Wiley-Liss, Inc.

Mizokami M.,The Research Center for Hepatitis and Immunology
Journal of Gastroenterology and Hepatology (Australia) | Year: 2012

Chronic hepatitis C affects 2.2-3.0% of the world population (130 million-170 million). Pegylated interferon-α (PEG-IFN-α) in combination with ribavirin (RBV), the approved and standard therapy, leads to viral eradication in about 50% of treated patients. In 2009, genome-wide association studies (GWAS) identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). A correlated set of polymorphisms in the region of the interleukin-28B (IL-28B) gene on chromosome 19, coding for interferon (IFN)-λ3 were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with PEG-IFN-α and RBV. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. In addition, prediction of viral response to PEG-IFN-α and RBV therapy of patients with recurrent HCV infection after orthotopic liver transplantation depends on the IL-28B genotype of both recipient and donor tissues. Diagnosis of a patient's IL-28B genotype is likely to aid in clinical decision making with standard-of-care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL-28B genotype. As GWAS yield unexpected data, this approach could lead to the development of novel drug therapy, such as already appears promising with IFN-λ. In this Okuda lecture, I present the current understanding in regard to the relationship between host variations and clinical outcome of hepatitis C. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Tatematsu K.,Nagoya City University | Tanaka Y.,Nagoya City University | Sugiyama M.,Nagoya City University | Sudoh M.,Chugai Pharmaceutical Co. | And 2 more authors.
Journal of Medical Virology | Year: 2011

Serine palmitoyltransferase (SPT) catalyzes the first step in the sphingolipid biosynthetic pathway. Myriocin inhibits SPT and was shown to suppress the replication of hepatitis C virus (HCV) in vitro and in vivo. However, its effect on hepatitis B virus (HBV) replication is unknown. In this study, the HBV DNA levels in HuH7 cell culture supernatants were lowered successfully by using myriocin and it was found that the 50% inhibitory concentration of myriocin is approximately 5μM. Myriocin and/or pegylated interferon (PEG-IFN) were also administered to chimeric mice for 2 weeks and the effects of these compounds on HBV DNA levels were determined. Myriocin alone did not reduce effectively the HBV DNA levels, whereas PEG-IFN alone reduced the DNA levels to 1/10th of the control levels. The combination of myriocin with PEG-IFN reduced the HBV levels to about 1/1,000th of the control levels and induced a 1.0log reduction in the levels of the HBV surface antigen and core protein. This latter effect was not observed in the other treatment groups. In conclusion, the combination of myriocin with PEG-IFN represses synergistically HBV replication in vivo without inducing hepatotoxicity. © 2011 Wiley-Liss, Inc.

Kawashima M.,University of Tokyo | Ohashi J.,University of Tsukuba | Nishida N.,University of Tokyo | Nishida N.,The Research Center for Hepatitis and Immunology | Tokunaga K.,University of Tokyo
PLoS ONE | Year: 2012

The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04:01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04:01. The DPB1*04:01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06:04 and DPB1*04:01 observed in Japanese cannot be explained without positive selection favoring DPB1*04:01. The selection coefficient of DPB1*04:01 was estimated as 0.041 (95% credible interval 0.021-0.077). Our results suggest that DPB1*04:01 has recently undergone strong positive selection in Japanese population. © 2012 Kawashima et al.

Mizokami M.,The Research Center for Hepatitis and Immunology
Uirusu | Year: 2012

Hepatitis B virus (HBV) prevention program in Japan is considered one of the most successful and effective public anti-counter programs to HBV infection. However, almost all of population under twenty-five years is extremely susceptibility for HBV infection. HBV genotype A, which was not in Japan and has been from western countries, is increasing in chronic hepatitis B patients in Japan as a consequence of acute hepatitis B spreading in the younger generation through promiscuous sexual transmitted infection and the characteristics of HBV genotype A is a prolonged high HBVDNA viremia compared with other HBV genotypes. These data have strongly indicated that the main transmission route of HBV in Japan has been changed to a horizontal infection with sexual transmitted disease from perinatal transmission from HBsAg positive mothers. Although the HBV vaccine has tipped the balance in our favor, newly issues of HBV vaccine has been arisen such as vaccine escape mutant, efficacy and potency for the prevention of HBV infection, especially different HBV genotypes, HBV reactivation on the patients with HBsAg negative and anti-HBs antibody positive under systemic chemotherapy, and universal vaccination or selective vaccination and so on.

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