Treatment of HCV patients with pegylated interferon and ribavirin results in a suppression of expression of mRNA for ribosomal proteins and factors involved in protein synthesis, in PBMC isolated from patients. This suppression is global for ribosomal proteins and eukaryotic translation factors and persists through out the treatment period up to 28 days. The extent of down regulation is approximately 50%.
We have previously reported the down regulation of a few individual ribosomal proteins and translation factors in PBMC in vitro and in vivo [5, 9] following treatment with Interferon/ribavirin. In this paper we show that this is a global effect on the transcription of ribosomal protein genes. We have examined the effect of ribavirin alone on PBMC in vitro and find some decrease in mitochondrial ribosomal protein transcription but not on cytoplasmic ribosomal proteins (data not shown). Jiang et al.  reported the suppression of ribosomal protein L23 transcription during growth of a melanoma in culture treated with interferon alpha, beta and gamma but in the absence of ribavirin.
Meier et al. 2003  reported the inhibition of DNA, RNA and protein synthesis in vitro on PBMC treated with PHA in the presence of high doses of ribavirin. This was a general effect and could be reversed by the addition of guanosine. A thorough analysis by Wadell et al.  shows a few ribosomal protein genes as being down regulated by IFN-beta and IFN-gamma in PBMC, although not by IFN-alpha. However the fold cut off used in these experiments as in our earlier experiments would not pick up the whole pathway. Thus it is likely that the combination of Interferon and ribavirin specifically affects transcription of the protein synthetic apparatus.
Unlike other genes affected by interferon/ribavirin treatment where we see transient changes in ISGs 6 days after interferon treatment, the down regulation of transcription of ribosomal proteins appears to be quite constant.
Interferon by itself has previously been shown to inhibit protein synthesis in a specific manner. This is through the dsRNA pathway in which RNAse L is activated and degrades viral RNA [14, 15]. However it is unlikely that this down regulation of ribosomal protein gene mRNA is the result of non-specific RNA degradation since there is no effect over all in amounts of specific RNA in the cell as judged by the large number of genes (the majority) not affected by interferon/ribavirin treatment.
PKR an interferon induced (and activated) enzyme has been shown to phosphorylate eukaryotic initiation factor (EIF2) resulting in inhibition of viral protein synthesis . Phosphorylation of eIF2 may have an effect on overall protein synthesis, however this is unlikely the case here since there is no evidence for general inhibition of protein synthesis. The expression of most genes is constant, and only a small percentage are either induced or suppressed. That viral protein synthesis in inhibited is shown by the decrease in viral titer during treatment in responding patients . However the decrease in ribosomal protein gene transcription occurs even in non-responding patients, although to a slightly lower level. This is in keeping with our previous data in which we have shown that in non-responsive patients there is a general blunting of the interferon/ribavirin effect .
MicroRNAs have been implicated in regulation of immune response in lymphocytes and in particular miRNA-146a has been shown to inhibit by a feed back mechanism the expression of interferon inducible genes. However a search of known microRNAs has not shown any relationship to ribosomal mRNA or Eukaryotic translation factors. It is possible that unknown microRNAs interact with common sequences in these genes and suppress transcription or degrade these RNAs. However this is purely speculative. We also were unable to find any common transcriptional regulatory sequence upstream of these genes. Previous reports [17–19] have indicated a possible role for c-myc in regulating ribosomal protein transcription, however level of c-myc at the transcription level is unaffected by interferon/ribavirin in our analysis. It is likely that as cells slow down in growth, and undergo apoptosis that the rate of ribosomal protein and other proteins involved in translation will also decrease. We have previously noted (unpublished data) that myc transcription is significantly down regulated in a b-cell line, Daudi following treatment with interferon-alpha. Thus the decrease reported here might reflect a decrease in ribosomal protein transcription in one class of immune cells.
The finding of a general decrease in the protein translation machinery would be an effective way of inhibiting virus. Viral load decrease often occurs in vivo a few days after the initial treatment with interferon/ribavirin. However this drug combination may also partially inhibit host protein synthesis in general, and lead to a variety of side effects in the patients. This could in part be an explanation for the flu like symptoms and anemia often seen in patients undergoing treatment with interferon/ribavirin. Whether this is due to interferon alone, or only occurs in the presence of ribavirin is not clear, although experiments in which PBMC were treated only with ribavirin did not show this effect on ribosomal proteins. However the levels used in these experiments may have been too low. This effect was not found in other cell lines treated with interferon in vitro and thus may be unique to PBMC  or to the combination treatment.