Expression of Hepatitis C Virus Proteins Interferes with the Antiviral Action of Interferon Independently of PKR-Mediated Control of Protein Synthesis

Abstract

-1271, 1999). In the present study we analyzed whether the resistance of UHCV-11 cells to IFN could also be attributed to inhibition of PKR. Confocal laser scanning microscopy showed no colocalization of PKR, which is diffuse throughout the cytoplasm, and the induced HCV proteins, which localize around the nucleus within the endoplasmic reticulum. The effect of expression of HCV proteins on PKR activity was assayed in a reporter assay and by direct analysis of the in vivo phosphorylation of eIF2␣ after treatment of cells with poly(I)-poly(C). We found that neither PKR activity nor eIF2␣ phosphorylation was affected by coexpression of the HCV proteins. In conclusion, expression of HCV proteins in their biological context interferes with the development of the antiviral action of IFN. Although the possibility that some inhibition of PKR (by either NS5A or another viral protein) occurs at a very localized level cannot be excluded, the resistance to IFN, resulting from the expression of the HCV proteins, cannot be explained solely by inhibition of the negative control of translation by PKR.

Expression of hepatitis C virus NS5A natural mutants in a hepatocytic cell line inhibits the antiviral effect of interferon in a PKR-independent manner

“…6, 2001 polyprotein expression on PKR activity. 37 Most importantly, recent evidence supporting our negative observation also stems from the development of HCV replicons expressing the HCV nonstructural proteins. 38 In this experimental model, it has indeed been shown that ISDR deletion does not modify sensitivity to IFN; in contrast, the results were consistent with a role of NS5A in HCV-RNA replication.…”

High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b–related cirrhosis

“…20 Nevertheless, HCV-interference of the antiviral activity of interferon by mechanisms unrelated to PKR-bd function is also possible, as recently observed. 67,70 Regulation of PKR probably implicates various cellular pathways that may be different depending on the cell type and stimulatory events. 71 In fact, HCV-NS5A seems to act over different cellular factors for the regulation of cellular metabolism, promoting cell growth and perturbing mitogenic signaling pathways.…”

Hepatitis C Virus Resistance to Antiviral Therapy

“…[101][102][103][104] Nevertheless, the existence of such interactions in vivo and their role in HCV resistance to IFN therapy are not convincingly supported by epidemiologic or biologic observations. [105][106][107][108] Viral polyprotein inhibition of the JakStat pathway (the main pathway responsible for IFN-␣ signal transduction) upstream of PKR has also been reported in vitro, but the involved mechanisms remain unknown. 109 Overall, several genome or viral protein functions, or both, and their interactions with numerous host cell functions are probably involved in HCV resistance to the nonspecific antiviral action of IFN-␣ in infected cells.…”