Cellular and Molecular Gastroenterology and Hepatology (Jan 2021)

Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional CureSummary

  • Takashi Honda,
  • Norie Yamada,
  • Asako Murayama,
  • Masaaki Shiina,
  • Hussein Hassan Aly,
  • Asuka Kato,
  • Takanori Ito,
  • Yoji Ishizu,
  • Teiji Kuzuya,
  • Masatoshi Ishigami,
  • Yoshiki Murakami,
  • Tomohisa Tanaka,
  • Kohji Moriishi,
  • Hironori Nishitsuji,
  • Kunitada Shimotohno,
  • Tetsuya Ishikawa,
  • Mitsuhiro Fujishiro,
  • Masamichi Muramatsu,
  • Takaji Wakita,
  • Takanobu Kato

Journal volume & issue
Vol. 12, no. 5
pp. 1583 – 1598

Abstract

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Background & Aims: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

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