Journal of Hepatology
Volume 54, Issue 1 , Pages 19-25, January 2011

Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion

  • Shuang Wu

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • ,
  • Fumio Imazeki

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • Corresponding Author InformationCorresponding author. Address: Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba 260-8670, Japan. Tel.: +81 43 226 2083; fax: +81 43 226 2088.
    • ,
  • Fuat Kurbanov

      Affiliations

    • Department of Virology, Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
    • ,
  • Kenichi Fukai

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • ,
  • Makoto Arai

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • ,
  • Tatsuo Kanda

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • ,
  • Yutaka Yonemitsu

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • ,
  • Yasuhito Tanaka

      Affiliations

    • Department of Virology, Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
    • ,
  • Masashi Mizokami

      Affiliations

    • Research Center for Hepatitis and Immunology, International Medical Center of Japan Kounodai Hospital, Ichikawa, Japan
    • ,
  • Osamu Yokosuka

      Affiliations

    • Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

Received 15 December 2009; received in revised form 4 June 2010; accepted 7 June 2010. published online 31 August 2010.

Background & Aims

Although the evolution of viral quasi-species may be related to the pathological status of disease, little is known about this phenomenon in hepatitis B, particularly with respect to hepatitis B e antigen (HBeAg) seroconversion.

Methods

Nucleotide sequences of the hepatitis B virus (HBV) X/precore/core region was analyzed at five time-points in four groups of chronic hepatitis B patients, interferon-induced seroconverters (IS, N=9), interferon non-responders (IN, N=9), spontaneous seroconverters (SS, N=9), and non-seroconverters (SN, N=9) followed during 60months on an average. Only patients with genotype C were studied.

Results

Analysis of 1800 nucleotide sequences showed that there was no statistical difference between the nucleotide genetic distances of seroconverters (IS and SS; 6.9×10−3 substitutions (st)/site and 6.7×10−3 st/site, respectively) and those of non-seroconverters (IN and SN; 5.3×10−3 st/site and 3.8×10−3 st/site, respectively) before seroconversion. Compared to non-seroconverters (IN and SN; 5.1×10−3 st/site and 5.9×10−3 st/site, respectively), the sequence diversity of seroconverters (IS and SS; 10.9×10−3 st/site and 9.9×10−3 st/site, respectively) was significantly higher after seroconversion (p<0.05), and was higher in seroconverters after seroconversion than before seroconversion (p<0.05), while this changed very little in non-seroconverters during the observation period. Phylogenetic trees showed greater complexity in secoconverters than non-seroconverters. Parsimony-based estimation of the direction of sequence change between descendants and ancestors before HBeAg seroconversion, revealed higher frequencies of transversional A to T substitution in seroconverters (0.06 vs. 0.02, p=0.0036) that coincided with the dynamics of quasi-species possessing A1762T mutation.

Conclusions

The distinctly greater viral diversity in HBeAg seroconverters after seroconversion could be related to escape mutants resulting from stronger selection pressure.

Keywords: Chronic hepatitis B, Quasi-species, Hepatitis B e antigen seroconversion

Abbreviations: SC, seroconversion, ALT, alanine aminotransferase, CHB, chronic hepatitis B, HBV, hepatitis B virus, IFN, interferon, HBeAg, hepatitis B e antigen, HBsAg, hepatitis B surface antigen, IS, interferon-induced HBeAg seroconverters, IN, IFN non-responders, SS, spontaneous seroconverters, SN, non-seroconverters

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PII: S0168-8278(10)00708-7

doi:10.1016/j.jhep.2010.06.018

Journal of Hepatology
Volume 54, Issue 1 , Pages 19-25, January 2011

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