The HCV NS3/4A-mediated impairment of the hepatic antiviral immune response is reversed by protease inhibition or ribavirin in vivo
E.D. Brenndörfer1*, A. Brass1, J. Söderholm2, L. Frelin1, J.G. Bode3, M. Sällberg1
1Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, 2Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 3Department of Gastroenterology, Hepatology and Infectiology, University Hospital, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany. *email@example.com
Background: Hepatitis C virus (HCV) has evolved mechanisms to evade
elimination by both innate and adaptive immunity resulting in HCV persistence.
The HCV NS3/4A protease/helicase is known to modulate signaling pathways in the
infected hepatocyte by cleaving MAVS, TC-PTP and TRIF. However, the global
effects exerted by NS3/4A in vivo
still remain unclear. This is currently of a particular interest since new
antiviral therapies are being introduced based on inhibitors blocking the
NS3/4A protease. Thus, these therapies may exert effects beyond the viral
Objectives: We aimed to understand how NS3/4A affects intercellular
signaling and immune cell function in
vivo and to study the effects of ribavirin or NS3/4A protease inhibition on
the NS3/4A-mediated modulation of the host's immune system.
Methods: The intrahepatic immune response of naive and
lipopolysaccharide (LPS)/D-galactosamine (D-galN) treated NS3/4A-transgenic
(Tg) mice was determined by western blot, ELISA, Real Time PCR, Flow cytometry,
ALT levels, and survival. Ribavirin pretreatment or NS3/4A protease inhibition
was performed to analyze the influence of antivirals on the NS3/4A-mediated
Results: Hepatic IL10 expression is enhanced in NS3/4A-Tg mice both
basally and after LPS/D-galN treatment, while IFNγ secretion is impaired. Furthermore, the chemokine profile
(CCL2, CCL17, CXCL9) is altered towards an anti-inflammatory state. As result,
the intrahepatic number of Th1 cells as well as IFNγ-positive CD4+ and CD8+ T cells in NS3/4A-Tg mice is decreased, while the
amount of Th2 cells is increased. Interestingly, the NS3/4A-mediated effects
could be reversed by both ribavirin treatment and inhibition of the NS3/4A
protease. This is of particular importance since recent clinical trials suggest
that ribavirin is essential for a functional therapy with only directly acting
antiviral (DAAs) compounds.
induces a shift of the intrahepatic immune response towards a non-antiviral Th2-dominated
immunity. This may impair the host response to the infection and promote viral
persistence. Importantly, both ribavirin treatment and the inhibition of the
NS3/4A protease can block the effects mediated by NS3/4A.