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

• Published in: Gut Vol. 58; no. 4; pp. 560 - 569
• Main Authors: Ahlén, G, Derk, E, Weiland, M, Jiao, J, Rahbin, N, Aleman, S, Peterson, D L, Pokrovskaja, K, Grandér, D, Frelin, L, Sällberg, M
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.04.2009; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Animals; Apoptosis; Biological and medical sciences; Biopsy; Disease Models, Animal; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes; Hepacivirus - immunology; Hepacivirus - metabolism; Hepatitis; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Hepatocytes - immunology; Hepatocytes - virology; Hepatology; Humans; Immunity, Innate; Infections; Interferon; Interferon-beta - immunology; Liver - metabolism; Liver Neoplasms - immunology; Lymphocytes; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred Strains; Mice, Transgenic; Mutation; NF-kappa B - metabolism; Patients; Plasmids; Proteins; RNA, Double-Stranded - immunology; Rodents; Species Specificity; Studies; T-Lymphocytes - immunology; Tumor Cells, Cultured; Viral infections; Viral Nonstructural Proteins - metabolism; Viruses; Virus; Hepatocyte; Immunological investigation; Gastroenterology; T-Lymphocyte; Cleavage; Flaviviridae; Hepatitis C virus; Hepacivirus
• DOI: 10.1136/gut.2007.147264
• ISSN: 0017-5749; 1468-3288

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.