Cleavage of the IPS-1/Cardif/MAVS/VISA does not inhibit T cell-mediated elimination of hepatitis C virus non-structural 3/4A-expressing hepatocytes. Issue 4 (8th August 2008)

• Record Type: Journal Article
• Authors: Ahlén, G; Derk, E; Weiland, M; Jiao, J; Rahbin, N; Aleman, S; Peterson, D L; Pokrovskaja, K; Grandér, D; Frelin, L; Sällberg, M
• Is Part Of: Gut. Volume 58:Issue 4(2009)
• Page Start: 560
• Page End: 569
• Publication Date: 2008-08-08
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2007.147264
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Hepatitis C virus (HCV) effectively establishes persistent infection in human livers. The non-structural (NS) 3/4A complex participates in this process by cleavage of interferon β (IFNβ) promoter stimulator-1 (IPS-1; also termed Cardif/MAVS/VISA), which inhibits responses to double stranded (ds) RNA. However, it is not known whether this effect extends beyond innate responses. Aims: To test if HCV NS3/4A affects innate and adaptive immune responses in vivo. Methods: NS3 levels were semi-quantified in human liver biopsies, transfected cells, and in transgenic (Tg) mouse livers by western blot. The effect of NS3/4A on dsRNA-mediated signalling and on the integrity of IPS-1 was analysed using in vitro translation, transfected cells and Tg mice. Cytotoxic T cell (CTL)-mediated clearance of transient firefly luciferase (FLuc)- and/or NS3/4A-Tg hepatocytes was determined using in vivo imaging and western blot. Results: NS3 protein levels were in a comparable range (0.1–49 μg/g tissue) in infected human livers and Tg mouse livers. Importantly, these levels of NS3/4A reduced murine innate responses to synthetic dsRNA in vivo, supporting the possibility that this occurs also in infected humans. The likely explanation for this was the NS3/4A-mediated cleavage of mouse IPS-1, albeit less efficiently than human IPS-1. Despite this, FLuc- and/or NS3/4A-expressing murine hepatocytes were effectively eliminated by hepatic CTLs, utilising the classical molecules for virus-infected cell lysis, including CD8, IFNγ, perforin and FasL. Conclusions: Although HCV NS3/4A inhibits the innate immunity, this does not prevent CTL-mediated clearance of NS3/4A-expressing hepatocytes in vivo. Thus, other HCV proteins are most likely responsible for interfering with the adaptive immunity.