Upregulation of Major Histocompatibility Complex Class I on Liver Cells by Hepatitis C Virus Core Protein via p53 and TAP1 Impairs Natural Killer Cell Cytotoxicity

Abstract

The mechanisms of immune evasion and the role of the early immune response in chronic infection caused by hepatitis C virus (HCV) are still unclear. Here, we present evidence for a cascade of molecular events that the virus initiates to subvert the innate immune attack. The HCV core protein induced p53-dependent gene expression of TAP1 (transporter associated with antigen processing 1) and consecutive major histocompatibility complex (MHC) class I upregulation. Moreover, in p53-deficient liver cell lines, only reconstitution with wild-type p53, but not mutated p53 lacking DNA binding capacity, showed this effect. As a consequence of increased MHC class I expression, a significantly downregulated cytotoxic activity of natural killer (NK) cells against HCV core-transfected liver cells was observed, whereas lysis by HCV-specific cytotoxic T cells was not affected. These results demonstrate a way in which HCV avoids recognition by NK cells that may contribute to the establishment of a chronic infection.Hepatitis C virus (HCV) acts as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. To date, HCV infection is one of the primary causes of liver transplantation in the United States and other countries. More than 170 million individuals have been reported to be seropositive worldwide (40). There is no sufficient prophylaxis by vaccination, and antiviral therapy with a combination of alpha interferon (IFN-␣) and ribavirin is effective only in selected patients. This underlines an urgent need to improve our knowledge of virus-cell interactions and immune escape mechanisms. Elucidation of the mechanisms by which HCV interacts with and regulates the immune response, especially in the early stages of infection, is likely to lead to productive insights into how to combat chronic infection and prevent its serious complications.HCV has been classified as the sole member of a distinct genus called Hepacivirus in the family Flaviviridae. The characteristic all of these viruses have in common is a positivestranded RNA that, in the case of HCV, consists of a genome of approximately 10 kb containing one large open reading frame (ORF) that is initially translated into one single polyprotein and subsequently cleaved into the functional proteins. The putative organization of the HCV genome includes the 5Ј-untranslated region, four structural proteins, six nonstructural proteins, and a 3Ј-untranslated region (41). Among the structural proteins of HCV, the basic 19-kDa core protein exhibits pleiotropic features. It may be involved in nucleocapsid formation, and it plays a role in the switch between viral polyprotein synthesis and subsequent viral RNA replication. In addition, HCV core protein was shown to transcriptionally regulate several cellular and viral genes (28). Furthermore, severalalthough in part contradictory-reports suggest an influence of the HCV core protein on the transcriptional activity of p53 and the regulation of p53-dependent genes. Both suppression and upregulation of p53-dependen...

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“…Flow cytometry. Cells were rinsed twice with PBS 36 h after stimulation, detached from culture dishes with PBS containing 20 mmol/L EDTA, washed, and resuspended in PBS supplemented with 5% FCS, essentially as described previously (23). Approximately 5 Â 10 5 cells were used per sample.…”

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