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Int. J. Mol. Sci. 2017, 18(11), 2346; https://doi.org/10.3390/ijms18112346

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

1
Ivanovsky Institute of Virology, Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia
2
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
*
Authors to whom correspondence should be addressed.
Received: 20 September 2017 / Revised: 27 October 2017 / Accepted: 3 November 2017 / Published: 6 November 2017
(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)
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Abstract

The hepatitis C virus (HCV) causes chronic liver disease leading to fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection triggers various types of cell death which contribute to hepatitis C pathogenesis. However, much is still unknown about the impact of viral proteins on them. Here we present the results of simultaneous immunocytochemical analysis of markers of apoptosis, autophagy, and necrosis in Huh7.5 cells expressing individual HCV proteins or their combinations, or harboring the virus replicon. Stable replication of the full-length HCV genome or transient expression of its core, Е1/Е2, NS3 and NS5B led to the death of 20–47% cells, 72 h posttransfection, whereas the expression of the NS4A/B, NS5A or NS3-NS5B polyprotein did not affect cell viability. HCV proteins caused different impacts on the activation of caspases-3, -8 and -9 and on DNA fragmentation. The structural core and E1/E2 proteins promoted apoptosis, whereas non-structural NS4A/B, NS5A, NS5B suppressed apoptosis by blocking various members of the caspase cascade. The majority of HCV proteins also enhanced autophagy, while NS5A also induced necrosis. As a result, the death of Huh7.5 cells expressing the HCV core was induced via apoptosis, the cells expressing NS3 and NS5B via autophagy-associated death, and the cells expressing E1/E2 glycoproteins or harboring HCV the replicon via both apoptosis and autophagy. View Full-Text
Keywords: hepatitis C virus; hepatoma Huh7.5 cells; apoptosis; autophagy; necrosis; caspase; replicon hepatitis C virus; hepatoma Huh7.5 cells; apoptosis; autophagy; necrosis; caspase; replicon
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Masalova, O.V.; Lesnova, E.I.; Solyev, P.N.; Zakirova, N.F.; Prassolov, V.S.; Kochetkov, S.N.; Ivanov, A.V.; Kushch, A.A. Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells. Int. J. Mol. Sci. 2017, 18, 2346.

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