Interferon signalling in the liver : implications for the natural course and therapy of hepatitis C

Hepatitis C virus is a global health concern, estimated to infect 2-3% of the world's population. Inter-individual differences in the course of infection and response to therapy, highlighted by recent genomewide association studies, point to the crucial role of the host immune system in the efficient control of infection. Ongoing progress in the studies of the role of innate immunity during hepatitis C virus infection has improved our understanding of the intricacies of the host-virus interactions. In this work I present and discuss results of three studies aimed to dissect interferon signalling in the liver in the context of natural course or therapy of hepatitis C virus infection.
Interferon-based therapies are in clinical use for treatment of diseases such as hepatitis C virus infection or multiple sclerosis. Interferon-induced regulators of the Jak-STAT signalling are known to involve in negative feedback loops and affect the response to exogenously administered interferon alpha. In this context it is important to understand which interferon subtypes are potent inducers of the negative regulators and whether all interferons are equally sensitive to the inhibitory mechanisms. To tackle this question we attempted to characterize and compare response patterns to interferons alpha, beta and lambda in a setting of continuous and repeated stimulation (see Section 3.1).
The acute phase of hepatitis C virus infection in humans (first 6 months after transmission) is characterized by high rates of spontaneous clearance and excellent treatment response (>90% cure rate). As the infection at that stage is mostly asymptomatic, it is rarely diagnosed and, in comparison to the chronic phase of hepatitis C virus infection, little is known about the human liver response to acute hepatitis C virus infection and the host-virus interactions during this time. In the second part of this PhD project we made use of the acute hepatitis C liver biopsies collected over the course of several years at the University Hospital of Basel to describe human hepatic response to acute hepatitis C virus infection and gain an insight into the mechanism of improved cure rate compared to chronic hepatitis C (see Section 3.2).
Chronic hepatitis C is currently treated with combination therapies based on pegylated interferon- alpha. A significant proportion of patients fails to respond to the current treatment options, probably due to the refractory state of the preactivated endogenous interferon system in the liver. Several compounds are currently in clinical development with the aim to improve the treatment outcome of pegylated interferon�alpha nonresponders. In the last part of this work we investigated in vivo the mode of action
of a novel synthetic TLR9 agonist which is a clinical candidate for anti-hepatitis C virus therapy
and characterized the hepatic response to this compound (see Section 3.3).