Mechanisms of immune evasion by hepatitis C virus and their role in establishment of viral persistence

• Antragsteller: Professor Dr. Volker Lohmann
• Fachliche Zuordnung: Virologie
• Förderung: Förderung von 2009 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 99161398

An estimated 170 million people worldwide are chronically infected with hepatitis C virus (HCV), leading in many cases to severe liver damage. The reasons for the high rate of persistence are not fully understood yet, but it is clear that the failure of innate and adaptive immune responses to eliminate the virus is of particular importance. During the first funding period TP3 analyzed interference of HCV with functional antigen presentation and escape of HCV from interferon-γ response, the central cytokine mediating noncytolitic T-cell response to HCV. An immunological model for authentic HLA-A2 restricted CD8+ T-cell response was established, providing a powerful system to study modulation of antigen presentation. The data of TP3 furthermore demonstrated that HCV persistence in presence of IFN-γ can be achieved and identified a number of novel candidate genes potentially involved in IFN-γ response to HCV. In continuation of this work we will analyze the functional role of fifty candidate genes differentially regulated in cell populations maintaining high levels of HCV replication in presence of efficient IFN-γ response. Validated candidates will be subjected to in depth studies on their mechanism of action. This work will reveal the contribution of IFN-γ resistance to HCV persistence and shed light on the general regulation of IFN-γ response and antiviral effector proteins targeting HCV. A second project will address the turnover of viral replication intermediates capable of activating innate immune responses. RNA replication generates huge amounts of viral pathogen associated molecular patterns (PAMPs), like double stranded RNA, which are recognized by cytosolic (RIG-I, MDA5) or endosomal (TLR3) pattern recognition receptors. During persistent infections viral PAMPs must undergo a regular turnover, this accounts particularly for double stranded replication intermediates contained in virus induced membrane vesicles. However, the pathway of decay of viral PAMPs has not been identified yet. Our work therefore aims to uncover the mechanism of disposal of viral replication intermediates and clarify its role in maintaining viral persistence. We will initially focus on the role of exosomes containing viral RNA. Exosomes have recently been found to be released by cells harboring subgenomic replicons and are capable of activating plasmacytoid dendritic cells (pDC). Modulation of virus induced exosome formation will reveal their function regarding regular turnover of viral RNA and circumventing activation of intracellular innate immune responses. Analysis of exosome secretion and pDC activation by other liver-tropic viruses causing acute infections will furthermore elucidate whether exosomes are a general phenomenon of positive strand RNA viruses or linked to persistent infections.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 1202: Mechanisms of persistence of hepatotropic viruses