G-to-A Hypermutation in Hepatitis B Virus (HBV) and Clinical Course of Patients with Chronic HBV Infection

Noguchi, Chiemi; Imamura, Michio; Tsuge, Masataka; Hiraga, Nobuhiko; Mori, Nami; Miki, Daiki; Kimura, Takashi; Takahashi, Shoichi; Fujimoto, Yoshifumi; Ochi, Hidenori; Abe, Hiromi; Maekawa, Toshiro; Tateno, Chise; Yoshizato, Katsutoshi; Chayama, Kazuaki
June 2009
Journal of Infectious Diseases;6/1/2009, Vol. 199 Issue 11, p1599
Academic Journal
Background. The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like family of cytidine deaminases induce G-to-A hypermutation in hepatitis B virus (HBV) genomes and play a role in innate antiviral immunity. The clinical relevance of this protein family is unknown. Methods. Weanalyzed 33 instances in which 17 patients with chronic HBV infection experienced >2 increases of >100 IU/L in alanine aminotransferase (ALT) level; we used a quantitative differential DNA denaturation polymerase chain reaction assay to quantify the hypermutated HBV genomes observed during 21 of these 33 increases in ALT level. Results. Of the 9 increases in ALT level that involved a >5-fold increase (relative to basal levels) in the number of hypermutated genomes observed, 8 were associated with a >2-log reduction in plasma HBV DNA level. In contrast, a corresponding decrease in plasma HBV DNA level was observed for only 1 of the 12 increases in ALT level that did not involve an increase in the number of hypermutated genomes (P < .001). Hepatitis B e antigen clearance was often observed in patients who experienced an increase in the number of hypermutated genomes. Interferon treatment induced hypermutation in HBV genomes in an animal model. However, there was no apparent increase in the number of hypermutated genomes among the majority of patients who received interferon therapy, probably because the number of hypermutated genomes had already increased prior to the initiation of therapy. Conclusion. Our results suggest that a marked increase in the number of hypermutated genomes represents a strong immunological host response against the virus and is predictive of hepatitis B e antigen clearance and plasma HBV DNA level reduction.


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