Shouichi Yokozaki

Difference of HBV Genotype Distribution Between Acute Hepatitis and Chronic Hepatitis in Japan

AbstractBackground:Recently genotype A which is rare in the patients in chronic hepatitis B (CHB) was frequently noted in patients with acute hepatitis B (AHB). To investigate their clinical and virological features, we studied the AHB patients in the past 5 years.Patients and Methods:98 patients with AHB and 80 patients with CHB admitted to our hospital between 1998 and 2003 were studied.Results:Genotype A was not found in CHB but was frequently noted in AHB (p < 0.001). Comparison of the clinical features of acute hepatitis between the two major genotypes, A and C, homosexual and heterosexual with multiple partners were frequently seen among genotype A patients (p < 0.001). On the other hand, infection from steady partner showed a tendency to be more frequent in genotype C (p = 0.065). In genotype A, the levels of HBVDNA on admission was higher (p = 0.007) and AHB has significantly more frequently progress to chronic infection than in genotype C (p = 0.028). Phylogenetic analysis of genotype A revealed that almost all strains from homosexual men belonged not to the African type A1 but to the Western type A2.Conclusion:Genotype A has increased recently among AHB in Japan. This fact may correlate to promiscuous intercourse in high risk group. Prophylactic efforts should be considered to prevent the prevailing of genotype A.

Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus‐infected haemophiliacs

We performed a pilot study to evaluate the factors associated with response to interferon (IFN) therapy for chronic hepatitis C (CHC) with human immunodeficiency virus (HIV) coinfected haemophiliacs. Seven haemophiliacs, coinfected with HIV and hepatitis C virus (HCV), received 9 mega‐units (MU) of natural IFN‐alpha daily during the first 2 weeks and then three times a week for 22 weeks, all injected subcutaneously. Six patients were receiving zidovudine (AZT) 600 mg day−1 and didanosine (ddI) 200 mg day−1 during IFN therapy. This treatment was safe and well tolerated. Four patients had no detectable serum HCV‐RNA at the end of therapy, but long‐term, none of the seven patients achieved a sustained response, i.e. undetectable serum HCV‐RNA with persistently normal serum alanine aminotransferase (ALT) 6 months after therapy. IFN did not affect CD4‐positive cell counts. Most of our patients had high HCV‐RNA loads and/or low CD4 counts, both unfavourable markers for IFN therapy. In conclusion, IFN therapy did not eradicate HCV from haemophiliacs coinfected with HIV.

Prevalence and characterization of hepatitis C virus genotype 4 in Japanese hepatitis C carriers

Hepatitis C virus (HCV) can be classified into six major genotypes, the prevalences of which differ around the world. In Japan, the main genotypes are HCV 1 and HCV 2; others are found only rarely. Little is known about the prevalence in Japan of HCV genotype 4 which, is found frequently in North and Central Africa and the Middle East. Thus, we conducted a study to clarify distribution of HCV genotype 4 and the clinical demographics of patients with HCV genotype 4 in Japan. We examined HCV genotypes in 899 Japanese individuals with HCV viremia living in Aichi Prefecture, including 63 hemophiliacs. Four patients (0.4%) were infected with HCV genotype 4. All four of these patients were male hemophiliacs who had received clotting factors from foreign countries. Three patients were co-infected with human immunodeficiency virus (HIV); none were co-infected with GB virus-C/hepatitis G virus. Phylogenetic analysis of the El region indicated that all four patients were infected with subtype 4a. This subtype is related genetically to a subtype previously reported in Japanese and Italian hemophiliacs. HCV genotype 4 is indeed rare in Japan and may be detected only among hemophiliacs who have received inactivated clotting factor concentrates from foreign countries.

Cloning and sequencing of a novel human gene that encodes a putative target protein of Nesh-SH3.

AbstractBy using a conventional two-hybrid technique with an Src homology 3 (SH3) domain of Nesh as the bait protein, a novel full-length cDNA was isolated and sequenced from a human placenta cDNA library. This cDNA consists of 3023 bp and has a predicted open reading frame that encodes 486 amino acids. It possesses an SH3 binding motif, a nuclear targeting sequence, and no catalytic domain. Overall, it has no similarity to known molecules involved in a signaling cascade. Polymerase Chair reaction-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels localized the gene on human chromosome 3q12 near the marker D3S1271.

Effects of HAART on hepatitis C, hepatitis G, and TT virus in multiply coinfected HIV-positive patients with haemophilia.

In multiply coinfected human immunodeficiency virus (HIV)‐positive patients, we investigated the effects of high‐activity antiretroviral therapy (HAART) using HIV protease inhibitors on three other viruses: hepatitis C virus (HCV), hepatitis G virus (HGV), and TT virus (TTV). Viral concentrations were measured serially by polymerase chain reaction methods in five patients with quadruple infection (HIV, HCV, HGV, and TTV) and in two patients with triple infection (HIV, HCV, and HGV) before and during HAART. In addition, CD4+ cell counts and serum alanine aminotransferase (ALT) levels were measured serially. Generally we observed no difference in serum HCV RNA, HGV RNA, or TTV DNA concentrations between samples obtained before and after initiation of HAART, whereas HIV RNA concentration decreased and CD4 counts increased in most patients. However, two patients had markedly decreased concentrations of HCV RNA and HGV RNA, respectively, more than 12 months after beginning HAART. Normalization of serum ALT levels was observed in a patient with decline of HCV RNA concentrations. No interactions were observed among these four viruses. HAART had no apparent direct effects on HCV, HGV, or TTV. Further studies will be required to elucidate whether the restoration of immune status through suppression of HIV replication by HAART may affect HCV or HGV RNA concentrations.

Mutations in two PKR-binding domains in chronic hepatitis C of genotype 3a and correlation with viral loads and interferon responsiveness

Interferon (IFN) induces the double‐stranded RNA‐dependent protein kinase (PKR) to inhibit viral replication. Two motifs of the PKR‐binding domain exist in the E2 and the NS5A regions of the hepatitis C virus (HCV). These regions are called the PKR‐eukaryotic transcription factor (elF2‐alpha) phosphorylation homology domain (PePHD), and the IFN sensitivity‐determining region (ISDR). Both regions are inhibited by PKR. Thus, several studies have reported the relationship between these regions and IFN responsiveness and the HCV viral load. However, the data obtained from these studies remain controversial. The aim of this study was to investigate the genomic heterogeneity of the PePHD and the ISDR in patients with genotype 3a and how this impacts HCV replication and the response to IFN therapy. Twenty‐one male patients infected with HCV genotype 3a were studied. The PePHD was well conserved, and mutations were found in only one amino acid position in two patients. Patients with three or more mutations in the ISDR had lower viral loads than those with fewer than two mutations (192.2 ± 176.7 vs. 1279.4 ± 997.6 KIU/ml, P = 0.0277). Ten (71.4%) of 14 patients achieved a sustained virological response to IFN therapy. No specific amino acid substitutions in the PePHD and the ISDR were associated with IFN responsiveness; however, the number of mutations in the ISDR was significantly associated with the HCV viral load. The findings from this study suggest that the ISDR plays an important role in regulating viral replication in patients infected with HCV genotype 3a. J. Med. Virol. 83:1727–1732, 2011.

The Expression of TIMP-3 in Hepatoma Cell Lines

Tissue inhibitors of metalloproteinases (TIMPs) constitute a family of proteins, of which four members have so far been identified. 1–4 TIMP-1 or -2 has been studied for liver fibrosis 5 or hepatoma invasion/metastasis. 6 TIMP-3, which has a similar structure to TIMP-1 and -2, has an ability to inhibit matrix metalloproteinases. It has been reported that TIMP-3 expression was increased in the tissues of breast cancer. 3