Article Text

other Versions

PDF
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
  1. Gustaf Ahlen (gustaf.ahlen{at}ki.se)
  1. Karolinska Institutet, Sweden
    1. Malin Weiland (malin.weiland{at}ki.se)
    1. Karolinska Institutet, Sweden
      1. Emma Derk (emma.derk{at}ki.se)
      1. Karolinska Institutet, Sweden
        1. Jian Jiao (jian.jiao{at}ki.se)
        1. Karolinska Institutet, Sweden
          1. Nogol Rahbin (nogol.rahbin{at}ki.se)
          1. Nogol Rahbin, Sweden
            1. Soo Aleman (soo.aleman{at}ki.se)
            1. Karolinska Institutet, Sweden
              1. Darrell L Peterson (dpeterso{at}mail2.vcu.edu)
              1. Virginia Commonwealth University, United States
                1. Katja Pokrovskaja (katja.pokrovskaja{at}ki.se)
                1. Karolinska Institutet, Sweden
                  1. Dan Grander (dan.grander{at}ki.se)
                  1. Karolinska Institutet, Sweden
                    1. Lars Frelin (lars.frelin{at}ki.se)
                    1. Karolinska Institutet, Sweden
                      1. Matti Sallberg (matti.sallberg{at}ki.se)
                      1. Karolinska Institutet, Sweden

                        Abstract

                        Background: The hepatitis C virus (HCV) effectively establishes persistent infection in human livers. The non-structural (NS) 3/4A complex participate in this process by cleavage of IFN-β 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 affect 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 signaling and on integrity of IPS-1 was analyzed using in vitro translation, transfected cells and Tg mice. Cytotoxic T cell (CTL)-mediated clearance of transiently Firefly luciferase (FLuc)- and/or NS3/4A-Tg hepatocytes was determined using in vivo imaging and western blot.

                        Results: NS3-protein levels were at somewhat 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 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 were FLuc- and/or NS3/4A-expressing murine hepatocytes effectively eliminated by hepatic CTLs, utilizing the classical molecules for virus-infected cell lysis, including CD8, IFN-γ, 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.

                        Statistics from Altmetric.com

                        Request permissions

                        If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.