The hepatitis C virus non-structural 3/4A protease activates Akt-dependent host cell signaling which is required for sufficient viral replication

• Published in: Zeitschrift für Gastroenterologie
• Main Authors: Brenndörfer, ED, Karthe, J, Cebula, P, Erhardt, A, Frelin, L, Schulte am Esch, J, Häussinger, D, Bode, JG, Sällberg, M
• Format: Conference Proceeding
• Language: English; German
• Published: 20.01.2009
• Subjects: EGF signaling; hepatitis C virus; phosphatase signaling; feedback inhibition
• ISSN: 0044-2771; 1439-7803
• DOI: 10.1055/s-0029-1191925

The hepatitis C virus (HCV) interferes with several cellular signaling pathways to warrant viral replication as well as survival of the infected cell and to protect the infected cell from antiviral efector mechanisms of the host. Thus it counteracts the interferon response to viral infection through non-structural 3/4A (NS3/4A) protease-mediated cleavage of CARDIF and TRIF thereby interrupting an important part of the innate antviral host response. The present study aimed to further clarify the interaction between NS3/4A and growth factor signaling of the host cell and its contribution to viral replication. We report that HCV NS3/4A-dependently suppresses T-cell protein tyrosine phosphatase (TC-PTP) expression through NS3/4A-dependent cleavage of TC-PTP. This down-regulation of TC-PTP leads to enhanced EGF-induced signal-transduction and increased basal as well as induced activity of Akt. Whereas Akt-activity is essential for sufficient viral replication activation of the EGF receptor and of its downstream efector the PI3-kinase are able to transmit enhancing effects of EGF on viral replication but not necesseraly required for viral replication. The enhanced activating phosphorylation of Akt may be due to a suppression of protein phosphatase (PP)2A activity through the enhanced tyrosine phosphorylation at tyrosine residue 307 that occurs in the absence of TC-PTP. Hence, our findings support the notion that therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects further diminishing viral replication. The NS3/4A inhibition reduces the processing of the viral polyprotein but also deprives HCV of modulating EGF-R signaling to its own purposes.