Persistent hepatitis C virus (HCV) infection can lead to chronic inflammation and even carcinogenesis. This may in part be due to various viral proteins, which affect apoptosis and promote liver cell growth. Recently, researchers reported a novel F protein, an alternative reading frame protein expressed from the HCV core coding sequence. The functional properties of this protein are presently unclear. Thus, we investigated whether F protein participates in the process of chronic HCV inflammation leading to malignant transformation. Serum or peripheral blood from 42 chronic HCV patients or 38 HCV-associated hepatocellular carcinoma (HCC) patients was analyzed for the presence of T lymphocytes and antibodies specific to F protein. Then, the correlation between indicators of F-specific immune response and viral load or serum IL-6 levels was examined. We identified the presence of both T- and B-cell-mediated immune responses specific to such an antigen in subjects with chronic HCV and in HCC patients. Of note, the presence of anti-F-specific antibodies appeared to be negatively correlated with HCV RNA viral load level. Furthermore, circulating IL-6 levels were significantly higher in patients with HCC than in those with chronic HCV. These increased serum IL-6 levels were, in some HCC patients, positively correlated with the presence of anti-F-specific antibodies. Taken together, these results suggest that F protein may participate in viral clearance and have anti-tumor effects, but may also contribute to the persistence of HCV infection in patients with a low viral load. This latter effect may cause hepatic damage leading to carcinogenesis. Elucidation of these F protein-associated contradictory functional activities is required.

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