Alterations in hepatitis B virus nucleotide sequences in a chronic virus carrier from immunotolerant to immunoactive phase

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Biochemical and Biophysical Research Communications

Volume 394, Issue 3, 9 April 2010, Pages 574-580

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doi:10.1016/j.bbrc.2010.03.022

Elsevier Inc. All rights reserved.

Alterations in hepatitis B virus nucleotide sequences in a chronic virus carrier

from immunotolerant to immunoactive phase

Kazuyoshi Ohkawaa, b, Tetsuo Takeharaa, Tomohide Tatsumia, Hisashi Ishidaa,

Matsuo Deguchic, Masanori Kagitac, Atsushi Hosuia, Takuya Miyagia, Kazuhiro

Katayamab and Norio Hayashia, ,

a Department of Gastroenterology and Hepatology, Osaka University Graduate

School of Medicine, 2-2, Yamadaoka, Suita 565-0871, Japan

b Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for

Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari-ku, Osaka

537-8511, Japan

c The Laboratory for Clinical Investigation, Osaka University Hospital, 2-15,

Yamadaoka, Suita 565-0871, Japan

Received 21 February 2010. Available online 7 March 2010.

Abstract

Factors involved in transition from the immunotolerant to immunoactive phase in

chronic hepatitis B virus (HBV) infection remain unclear. We investigated viral

mutations occurring during transition and elucidated their virological and

immunological significance. Full-length HBV DNA sequences were serially

determined in a chronic HBV carrier from the immunotolerant to immunoactive

phase. Viral replicative competence was examined by transfection analysis.

HBV-specific CD8+ T cell response was evaluated by coculture of CD8+ T cells

with autologous dendritic cells followed by interferon-ã Elispot assay. Eleven

point mutations and two deletions appeared around the onset of the immunoactive

phase. Viral replicative competence declined significantly after the onset of

active hepatitis. Examination of the CD8+ T cell response against two putative

T-cell epitopes, which contained substituted amino acids from the immunotolerant

to immunoactive phase, showed that mutant HBV epitopes gave a lesser T cell

response than wild-type HBV ones. In summary, point mutations and deletions may

occur prior to or concurrent with the onset of the immunoactive phase during

chronic HBV infection. These mutations may result in a significant decrease in

both viral replicative competence and HBV-specific CD8+ T cell response,

suggesting a possible adaptation for the maintenance of viral persistence.