TY - JOUR
T1 - A substitution in the pre-S1 promoter region is associated with the viral regulation of hepatitis B virus
AU - Ogura, Suguru
AU - Tameda, Masahiko
AU - Sugimoto, Kazushi
AU - Ikejiri, Makoto
AU - Usui, Masanobu
AU - Ito, Masaaki
AU - Takei, Yoshiyuki
N1 - Funding Information:
Masaaki Ito received honoraria for lecture fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd. and Takeda Pharmaceutical Co., Ltd., and departmental scholarship funds from Bristol-Myers Squibb, MSD K.K., Shionogi & Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Daiichi Sankyo Co., Ltd. Yoshiyuki Takei received honoraria for lecture fees from Otsuka Pharmaceutical Co., Ltd. and departmental scholarship funds from Astellas Pharma Inc., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Suntory Global Innovation Center Ltd. and Kyokuto Pharmaceutical Industrial Co. Ltd. The companies associated with this funding were not involved in the preparation of the manuscript or the decision to publish the present study. The other authors declare no conflicts of interest in association with the present study.
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/5/2
Y1 - 2019/5/2
N2 - Background: Much evidence has demonstrated the influence of Hepatitis B virus (HBV) mutations on the clinical course of HBV infection. As large (L) protein plays a crucial role for viral entry, we hypothesized that mutations in the pre-S1 promoter region might affect the expression of L protein and subsequently change the biological characters of virus. Methods: Patients infected with genotype C HBV were enrolled for analysis. HBV DNA sequences were inserted into a TA cloning vector and analyzed. To evaluate the effects of mutations in the pre-S1 promoter region, promoter activity and the expression of mRNA and L protein were analyzed using HepG2 cells. Results: In total, 35 patients were enrolled and 13 patients (37.1%) had a single base substitution in the pre-S1 promoter region; the most frequent substitution was a G-to-A substitution at the 2765th base (G2765A) in the Sp1 region. The HBV viral load showed a negative correlation with the substitution ratio of the Sp1 region or G2765A (r = - 0.493 and - 0.473, respectively). Among those with a viral load ≤5.0 log IU/ml, patients with the G2765A substitution showed a significantly lower HBV viral load than those with the wild-type sequence. HepG2 cells transfected with the G2765A substitution vector showed reduced luciferase activity of the pre-S1 promoter, as well as reduced expression of pre-S1 mRNA and L protein. Furthermore, the G2765A substitution greatly reduced the L protein expression level of vector-produced virus particles. Conclusion: G2765A substitution in the pre-S1 promoter reduced the expression of L protein and resulted in a low viral load and less severe disease in chronic HBV infections.
AB - Background: Much evidence has demonstrated the influence of Hepatitis B virus (HBV) mutations on the clinical course of HBV infection. As large (L) protein plays a crucial role for viral entry, we hypothesized that mutations in the pre-S1 promoter region might affect the expression of L protein and subsequently change the biological characters of virus. Methods: Patients infected with genotype C HBV were enrolled for analysis. HBV DNA sequences were inserted into a TA cloning vector and analyzed. To evaluate the effects of mutations in the pre-S1 promoter region, promoter activity and the expression of mRNA and L protein were analyzed using HepG2 cells. Results: In total, 35 patients were enrolled and 13 patients (37.1%) had a single base substitution in the pre-S1 promoter region; the most frequent substitution was a G-to-A substitution at the 2765th base (G2765A) in the Sp1 region. The HBV viral load showed a negative correlation with the substitution ratio of the Sp1 region or G2765A (r = - 0.493 and - 0.473, respectively). Among those with a viral load ≤5.0 log IU/ml, patients with the G2765A substitution showed a significantly lower HBV viral load than those with the wild-type sequence. HepG2 cells transfected with the G2765A substitution vector showed reduced luciferase activity of the pre-S1 promoter, as well as reduced expression of pre-S1 mRNA and L protein. Furthermore, the G2765A substitution greatly reduced the L protein expression level of vector-produced virus particles. Conclusion: G2765A substitution in the pre-S1 promoter reduced the expression of L protein and resulted in a low viral load and less severe disease in chronic HBV infections.
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U2 - 10.1186/s12985-019-1169-x
DO - 10.1186/s12985-019-1169-x
M3 - Article
C2 - 31046787
AN - SCOPUS:85065231482
VL - 16
JO - Virology Journal
JF - Virology Journal
SN - 1743-422X
IS - 1
M1 - 59
ER -