A substitution in the pre-S1 promoter region is associated with the viral regulation of hepatitis B virus
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RESEARCH
Open Access
A substitution in the pre-S1 promoter region is associated with the viral regulation of hepatitis B virus Suguru Ogura1†, Masahiko Tameda1†, Kazushi Sugimoto1,2*, Makoto Ikejiri2, Masanobu Usui3, Masaaki Ito4 and Yoshiyuki Takei1
Abstract 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. Keywords: Hepatitis B virus, Mutation, Pre-S1 promoter, L protein
Background Despite the promotion of vaccination, HBV infection remains one of the leading causes of severe liver disease, such as liver cirrhosis and HCC. According to the World Health Organization, an estimated 257 million people worldwide are currently infected chronically with HBV, and a higher prevalence is found among populations in African and western pacific regions [1]. As of 2011, 1.2 million people in Japan are estimated to be infected with * Correspondence: [email protected] † Suguru Ogura and Masahiko Tameda contributed equally to this work. 1 Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan 2 Department of Central Laboratory, Mie University Hospital, Tsu, Japan Full list of author information is available at the end of the article
HBV [2], and genotype C has been reported to be the most dominant strain in Japan, accounting for more than 80% of the chronic infections [3]. HBV is a hepatotropic DNA virus that belongs to the Hepadnavi
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