A novel anti-HBV agent, E-CFCP, restores Hepatitis B virus (HBV)-induced senescence-associated cellular marker perturbation in human hepatocytes

Yuki Takamatsu; Sanae Hayashi; Hiroki Kumamoto; Shuhei Imoto; Yasuhito Tanaka; Hiroaki Mitsuya; Nobuyo Higashi-Kuwata

doi:10.1016/j.virusres.2023.199094

A novel anti-HBV agent, E-CFCP, restores Hepatitis B virus (HBV)-induced senescence-associated cellular marker perturbation in human hepatocytes

Virus Res. 2023 May:329:199094. doi: 10.1016/j.virusres.2023.199094. Epub 2023 Mar 23.

Authors

Yuki Takamatsu¹, Sanae Hayashi², Hiroki Kumamoto³, Shuhei Imoto⁴, Yasuhito Tanaka², Hiroaki Mitsuya⁵, Nobuyo Higashi-Kuwata⁶

Affiliations

¹ Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan.
² Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo, Kumamoto, 860-8556 Japan; Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho, Nagoya, 467-8601 Japan.
³ Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, lna-machi, Kitaadachi-gun, Saitama, 362-0806 Japan.
⁴ Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi, Kumamoto 860-0082 Japan.
⁵ Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 5A11, Bethesda, MD 20892-1868 USA; Department of Clinical Sciences, Kumamoto University Hospital, 1-1-1 Honjo, Chuo, Kumamoto, 860-8556 Japan.
⁶ Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan. Electronic address: nkuwata@ri.ncgm.go.jp.

Abstract

Cellular senescence is a cellular state with a broad spectrum of age-related physiological conditions that can be affected by various infectious diseases and treatments. Therapy of hepatitis B virus (HBV) infection with nucleos(t)ide analogs [NA(s)] is well established and benefits many HBV-infected patients, but requires long-term, perhaps lifelong, medication. In addition to the effects of HBV infection, the effects of NA administration on hepatocellular senescence are still unclear. This study investigated how HBV infection and NA treatment influence cellular senescence in human hepatocytes and humanized-liver chimeric mice chronically infected with live HBV. HBV infection upregulates or downregulates multiple cellular markers including senescence-associated β-galactosidase (SA-β-Gal) activity and cell cycle regulatory proteins (e.g., p21^CIP1) expression level in hepatocellular nuclei and humanized-mice liver. A novel highly potent anti-HBV NA, E-CFCP, per se did not have significant disturbance on markers evaluated. Besides, E-CFCP treatment restored HBV-infected cells to their physiological phenotypes that are comparable to the HBV-uninfected cells. The results reported here demonstrate that, regardless of the mechanism(s), chronic HBV infection perturbates multiple senescence-associated markers in human hepatocytes and humanized-mice liver, but E-CFCP can restore this phenomenon.

Keywords: Cellular senescence; Hepatitis b virus; Human hepatocytes; Nucleoside analogs; p21(CIP1).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hepatitis B virus / genetics
Hepatitis B* / drug therapy
Hepatitis B* / metabolism
Hepatitis B, Chronic*
Hepatocytes
Humans
Mice