Background: Hepatitis C virus (HCV) infects approximately 3% of the world population and is the leading cause of liverdisease, impacting hepatocyte metabolism, depending on virus genotype. Hepatic metabolic functions show rhythmicfluctuations with 24-h periodicity (circadian), driven by molecular clockworks ticking through translational-transcriptionalfeedback loops, operated by a set of genes, called clock genes, encoding circadian proteins. Disruption of biologic clocks isimplicated in a variety of disorders including fatty liver disease, obesity and diabetes. The relation between HCV replicationand the circadian clock is unknown.Methods: We investigated the relationship between HCV core infection and viral replication and the expression of clockgenes (Rev-Erba, Rora, ARNTL, ARNTL2, CLOCK, PER1, PER2, PER3, CRY1 and CRY2) in two cellular models, the Huh-7 cellstransiently expressing the HCV core protein genotypes 1b or 3a, and the OR6 cells stably harboring the full-length hepatitisC genotype 1b replicon, and in human liver biopsies, using qRT-PCR, immunoblotting, luciferase assays andimmunohistochemistry.Results: In Huh-7 cells expressing the HCV core protein genotype 1b, but not 3a, and in OR6 cells, transcript and proteinlevels of PER2 and CRY2 were downregulated. Overexpression of PER2 led to a consistent decrease in HCV RNA replicatinglevels 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 mayimprove the effectiveness of HCV antiviral therapy. This would extend to hepatic viral infections the current spectrum ofchronotherapies, implemented to treat metabolic, immune related and neoplastic disease.
|Numero di pagine||10|
|Stato di pubblicazione||Published - 2013|
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)