Mutual Antagonism between Circadian Protein Period 2 and Hepatitis C Virus Replication in Hepatocytes

Giorgia Benegiamo, Gianluigi Mazzoccoli, Francesco Cappello, Francesca Rappa, Nunzia Scibetta, Jude Oben, Azzura Greco, Roger Williams, Angelo Andriulli, Manlio Vinciguerra, Valerio Pazienza

Research output: Contribution to journalArticle

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Abstract

Background: Hepatitis C virus (HCV) infects approximately 3% of the world population and is the leading cause of liver disease, impacting hepatocyte metabolism, depending on virus genotype. Hepatic metabolic functions show rhythmic fluctuations with 24-h periodicity (circadian), driven by molecular clockworks ticking through translational-transcriptional feedback loops, operated by a set of genes, called clock genes, encoding circadian proteins. Disruption of biologic clocks is implicated in a variety of disorders including fatty liver disease, obesity and diabetes. The relation between HCV replication and the circadian clock is unknown. Methods: We investigated the relationship between HCV core infection and viral replication and the expression of clock genes (Rev-Erbα, Rorα, ARNTL, ARNTL2, CLOCK, PER1, PER2, PER3, CRY1 and CRY2) in two cellular models, the Huh-7 cells transiently expressing the HCV core protein genotypes 1b or 3a, and the OR6 cells stably harboring the full-length hepatitis C genotype 1b replicon, and in human liver biopsies, using qRT-PCR, immunoblotting, luciferase assays and immunohistochemistry. Results: In Huh-7 cells expressing the HCV core protein genotype 1b, but not 3a, and in OR6 cells, transcript and protein levels of PER2 and CRY2 were downregulated. Overexpression of PER2 led to a consistent decrease in HCV RNA replicating levels and restoration of altered expression pattern of a subset of interferon stimulated genes (ISGs) in OR6 cells. Furthermore, in liver biopsies from HCV genotype 1b infected patients, PER2 was markedly localized to the nucleus, consistent with an auto-inhibitory transcriptional feedback loop. Conclusions: HCV can modulate hepatic clock gene machinery, and the circadian protein PER2 counteracts viral replication. Further understanding of circadian regulation of HCV replication and rhythmic patterns of host-hosted relationship may improve the effectiveness of HCV antiviral therapy. This would extend to hepatic viral infections the current spectrum of chronotherapies, implemented to treat metabolic, immune related and neoplastic disease.

Original languageEnglish
Article numbere60527
JournalPLoS One
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 8 2013

Fingerprint

Period Circadian Proteins
Hepatitis C virus
Virus Replication
virus replication
Viruses
Hepacivirus
hepatocytes
Hepatocytes
Clocks
Genotype
Liver
proteins
Genes
liver
genotype
Virus Diseases
Biopsy
Liver Diseases
liver diseases
rev Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mutual Antagonism between Circadian Protein Period 2 and Hepatitis C Virus Replication in Hepatocytes. / Benegiamo, Giorgia; Mazzoccoli, Gianluigi; Cappello, Francesco; Rappa, Francesca; Scibetta, Nunzia; Oben, Jude; Greco, Azzura; Williams, Roger; Andriulli, Angelo; Vinciguerra, Manlio; Pazienza, Valerio.

In: PLoS One, Vol. 8, No. 4, e60527, 08.04.2013.

Research output: Contribution to journalArticle

Benegiamo, G, Mazzoccoli, G, Cappello, F, Rappa, F, Scibetta, N, Oben, J, Greco, A, Williams, R, Andriulli, A, Vinciguerra, M & Pazienza, V 2013, 'Mutual Antagonism between Circadian Protein Period 2 and Hepatitis C Virus Replication in Hepatocytes', PLoS One, vol. 8, no. 4, e60527. https://doi.org/10.1371/journal.pone.0060527
Benegiamo, Giorgia ; Mazzoccoli, Gianluigi ; Cappello, Francesco ; Rappa, Francesca ; Scibetta, Nunzia ; Oben, Jude ; Greco, Azzura ; Williams, Roger ; Andriulli, Angelo ; Vinciguerra, Manlio ; Pazienza, Valerio. / Mutual Antagonism between Circadian Protein Period 2 and Hepatitis C Virus Replication in Hepatocytes. In: PLoS One. 2013 ; Vol. 8, No. 4.
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AU - Scibetta, Nunzia

AU - Oben, Jude

AU - Greco, Azzura

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