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Journal of Virology, November 2008, p. 10375-10385, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00395-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway

Lin Deng,¹ Tetsuya Adachi,¹ Kikumi Kitayama,¹ Yasuaki Bungyoku,¹ Sohei Kitazawa,² Satoshi Ishido,³ Ikuo Shoji,¹ and Hak Hotta^1*

Divisions of Microbiology,¹ Molecular Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017,² Laboratory for Infectious Immunity, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan³

Received 23 February 2008/ Accepted 20 August 2008

We previously reported that cells harboring the hepatitis C virus (HCV) RNA replicon as well as those expressing HCV NS3/4A exhibited increased sensitivity to suboptimal doses of apoptotic stimuli to undergo mitochondrion-mediated apoptosis (Y. Nomura-Takigawa, et al., J. Gen. Virol. 87:1935-1945, 2006). Little is known, however, about whether or not HCV infection induces apoptosis of the virus-infected cells. In this study, by using the chimeric J6/JFH1 strain of HCV genotype 2a, we demonstrated that HCV infection induced cell death in Huh7.5 cells. The cell death was associated with activation of caspase 3, nuclear translocation of activated caspase 3, and cleavage of DNA repair enzyme poly(ADP-ribose) polymerase, which is known to be an important substrate for activated caspase 3. These results suggest that HCV-induced cell death is, in fact, apoptosis. Moreover, HCV infection activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change and its increased accumulation on mitochondrial membranes. Concomitantly, HCV infection induced disruption of mitochondrial transmembrane potential, followed by mitochondrial swelling and release of cytochrome c from mitochondria. HCV infection also caused oxidative stress via increased production of mitochondrial superoxide. On the other hand, HCV infection did not mediate increased expression of glucose-regulated protein 78 (GRP78) or GRP94, which are known as endoplasmic reticulum (ER) stress-induced proteins; this result suggests that ER stress is not primarily involved in HCV-induced apoptosis in our experimental system. Taken together, our present results suggest that HCV infection induces apoptosis of the host cell through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway(s).

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* Corresponding author. Mailing address: Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5500. Fax: 81-78-382-5519. E-mail: hotta{at}kobe-u.ac.jp

Published ahead of print on 3 September 2008.

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Journal of Virology, November 2008, p. 10375-10385, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00395-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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