The fourth component of human
complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with
chronic hepatitis C virus (HCV)
infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV
infections displayed significantly lower C4
mRNA levels than liver tissue samples from patients with unrelated
liver disease. Further, C4
mRNA levels of the two
isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with
RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4
mRNA.
Gamma interferon (IFN-γ)-induced C4 promoter activation was also impaired in the presence of HCV
proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a
transcription factor important for basal C4 expression. On the other hand, the expression of
interferon regulatory factor 1 (IRF-1), which is important for IFN-γ-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV
proteins in innate immune regulation in establishing a
chronic infection.