Abstract
BackgroundWe have previously reported the induction of many interferon stimulated genes (ISGs) in PBMC collected from patients infected with HCV at various times after initiation of interferon-ribavirin treatment using DNA microarrays to identify changes in gene expression with time. Almost as many genes are down regulated (suppressed) during interferon-ribavirin treatment as are up regulated.MethodsDNA microarrays were analyzed by different software, including MAS5 (Affymetrix-Kegg) and GSEA (gene set enrichment analysis) to identify specific pathways both up regulated and down regulated. Data was assessed from a clinical trial, which was a microarray analysis from 68 patients.ResultsUp regulated genes included genes associated with NF-kb, toll like receptor cytokine -cytokine interaction, and complement and adhesion pathways. The most prominent pathway down regulated was that for ribosomal structural proteins, and eukaryotic translational factors. Down regulation of ribosomal protein genes continued through the treatment up to the last measurement, which was at day 28.ConclusionsThis suppression of the protein synthetic apparatus might explain the long-term side effects of interferon-ribavirin, and explain a non-specific effect of interferon-ribavirin on viral protein synthesis. There was no evidence for unique transcription factors or micro RNA involvement.
Highlights
Hepatitis C virus (HCV) infection is a significant global public health problem, affecting approximately 150 million individuals worldwide and over 4 million in the United States alone, where it is the predominant blood-borne infection [1]
We have previously reported that the transcription of a large number of genes is induced or increased above background in Peripheral Blood Mononuclear Cell (PBMC) harvested from patients with hepatitis C during the course of treatment with pegylatedInterferon-alpha (Pegasys) and ribavirin [5,8] the transcription of an equal number of genes is downregulated we have not previously attempted to classify them by pathway analysis
The only pathway down regulated at the level of False Detection Rate (FDR), 0.25 in this group of patients following treatment is the ribosomal pathway including ribosomal proteins initiation factors and elongation factors required for protein synthesis
Summary
Hepatitis C virus (HCV) infection is a significant global public health problem, affecting approximately 150 million individuals worldwide and over 4 million in the United States alone, where it is the predominant blood-borne infection [1]. It is currently the leading indication for a liver transplant and is responsible for 8,000-10,000 deaths annually. We have previously reported the induction of many interferon stimulated genes (ISGs) in PBMC collected from patients infected with HCV at various times after initiation of interferon-ribavirin treatment using DNA microarrays to identify changes in gene expression with time. Almost as many genes are down regulated (suppressed) during interferon-ribavirin treatment as are up regulated
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