The Research Center for Hepatitis and Immunology

Ichikawa, Japan

The Research Center for Hepatitis and Immunology

Ichikawa, Japan

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Miyakawa K.,Yokohama City University | Matsunaga S.,Yokohama City University | Watashi K.,Japan National Institute of Infectious Diseases | Sugiyama M.,The Research Center for Hepatitis and Immunology | And 5 more authors.
Oncotarget | Year: 2015

Viruses have evolved various strategies to escape from the innate cellular mechanisms inhibiting viral replication and spread. Extensive evidence has highlighted the ineffectiveness of interferon (IFN) therapy against chronic hepatitis B virus (HBV) infection, implying the existence of mechanisms by which HBV evades IFN-induced antiviral responses. In our current study, we demonstrate that HBV surface protein (HBs) plays a crucial role in counteracting the IFN-induced antiviral response mediated by tetherin (also known as BST-2). The type I IFN treatment of HBV-producing cells marginally but significantly inhibited the release of HBsAg and viral DNA, but this release was recovered by the knockdown of tetherin. HBs can interact with tetherin via its fourth transmembrane domain thereby inhibiting its dimerization and antiviral activity. The expression of a tetherin mutant devoid of the HBs-binding domain promoted a prominent restriction of HBV particle production that eventually resulted in the alleviation of caspase-1-mediated cytotoxicity and interleukin-1ß secretion in induced pluripotent stem cell (iPSC)-derived hepatocytes. Our current results thus reveal a previously undescribed molecular link between HBV and tetherin during the course of an IFN-induced antiviral response. In addition, strategies to augment the antiviral activity of tetherin by impeding tetherin-HBs interactions may be viable as a therapeutic intervention against HBV.


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.


Nakano T.,Mie University | Lau G.M.G.,University of California at Berkeley | Lau G.M.L.,University of California at Los Angeles | Sugiyama M.,The Research Center for Hepatitis and Immunology | Mizokami M.,The Research Center for Hepatitis and Immunology
Liver International | Year: 2012

Background: The hepatitis C virus (HCV) genomic database is expanding rapidly. Aims: There is a need to provide an updated phylogenetic tree analysis based on the complete coding region of HCV. Methods: All available HCV complete genome sequences in the HCV databases available through October 2010 were analyzed. Results: The assignment of all known complete sequences up-to-date confirmed the previous six major genotypes and one new sequence, which have been provisionally assigned as subtype 7a. New recombinant forms of HCV, although uncommon, have been detected and were found to have different crossover points. Conclusion: This updated analysis based on the complete region of HCV confirmed the validity of the previously assigned genotypes/subtypes and provided an up-to-date reference for future basic research and clinical studies. © 2011 John Wiley & Sons A/S.


Sugiyama M.,The Research Center for Hepatitis and Immunology | Sugiyama M.,Nagoya City University | Sugiyama M.,Japan Society for the Promotion of Science | Tanaka Y.,Nagoya City University | And 3 more authors.
PLoS ONE | Year: 2011

The current standard of care for the treatment of chronic hepatitis C is pegylated interferon-α (PEG-IFNα) and ribavirin (RBV). The treatment achieves a sustained viral clearance in only approximately 50% of patients. Recent whole genome association studies revealed that single nucleotide polymorphisms (SNPs) around IL-28B have been associated with response to the standard therapy and could predict treatment responses at approximately 80%. However, it is not clear which SNP is most informative because the genomic region containing significant SNPs shows strong linkage disequilibrium. We focused on SNPs in close proximity to the IL-28B gene to evaluate the function of each and identify the SNP affecting the IL-28B expression level most. The structures of IL-28A/B from 5′ to 3′-UTR were determined by complete cDNA cloning. Both IL-28A and 28B genes consisted of 6 exons, differing from the CCDS data of NCBI. Two intron SNPs and a nonsynonymous SNP did not affect IL-28B gene function and expression levels but a SNP located in the proximal promoter region influenced gene expression. A (TA) dinucleotide repeat, rs72258881, located in the promoter region was discovered by our functional studies of the proximal SNPs upstream of IL-28B; the transcriptional activity of the promoter increased gradually in a (TA) n length-dependent manner following IFN-α and lipopolysaccharide stimulation. Healthy Japanese donors exhibited a broad range of (TA) dinucleotide repeat numbers from 10 to 18 and the most prevalent genotype was 12/12 (75%), differing from the database (13/13). However, genetic variation of IL-28A corresponding to that of IL-28B was not detected in these Japanese donors. These findings suggest that the dinucleotide repeat could be associated with the transcriptional activity of IL-28B as well as being a marker to improve the prediction of the response to interferon-based hepatitis C virus treatment. © 2011 Sugiyama et al.


Yamasaki K.,National Hospital Organization | Tateyama M.,Kumamoto University | Abiru S.,National Hospital Organization | Komori A.,National Hospital Organization | And 14 more authors.
Hepatology | Year: 2014

The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We evaluated the ability of WFA+-M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+-M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA+-M2BP, and the response to interferon (IFN) therapy. Serum WFA+-M2BP levels were significantly increased according to the progression of liver fibrosis stage (P<0.001). In each distinctive stage of fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+-M2BP. Multivariate analysis identified age >57 years, F4, AFP >20 ng/mL, WFA+-M2BP ≥4, and WFA+-M2BP 1-4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time-dependent areas under the receiver operating characteristic curve demonstrated that the WFA+-M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP. Conclusion: WFA+-M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy. (Hepatology 2014;60:1563-1570). © 2014 The Authors.


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
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.


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.


Yoshio S.,The Research Center for Hepatitis and Immunology | Kanto T.,The Research Center for Hepatitis and Immunology
Journal of Gastroenterology | Year: 2016

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-λ3), remains to be elucidated. Human BDCA3+DCs have also been shown to be a potent producer of IFN-λ3 in HCV infection, suggesting the possibility that BDCA3+DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection. © 2016, Japanese Society of Gastroenterology.

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