Mouse models of acute and chronic hepacivirus infection

TY - JOUR

T1 - Mouse models of acute and chronic hepacivirus infection

AU - Billerbeck, Eva

AU - Wolfisberg, Raphael

AU - Fahnøe, Ulrik

AU - Xiao, Jing W.

AU - Quirk, Corrine

AU - Luna, Joseph M

AU - Cullen, John M

AU - Hartlage, Alex S.

AU - Chiriboga, Luis

AU - Ghoshal, Kalpana

AU - Lipkin, W Ian

AU - Bukh, Jens

AU - Scheel, Troels K.H.

AU - Kapoor, Amit

AU - Rice, Charles M

PY - 2017

Y1 - 2017

N2 - An estimated 71 million people worldwide are infected with hepatitis C virus (HCV). The lack of small-animal models has impeded studies of antiviral immune mechanisms. Here we show that an HCV-related hepacivirus discovered in Norway rats can establish high-titer hepatotropic infections in laboratory mice with immunological features resembling those seen in human viral hepatitis. Whereas immune-compromised mice developed persistent infection, immune-competent mice cleared the virus within 3 to 5 weeks. Acute clearance was T cell dependent and associated with liver injury. Transient depletion of CD4+ T cells before infection resulted in chronic infection, characterized by high levels of intrahepatic regulatory T cells and expression of inhibitory molecules on intrahepatic CD8+ T cells. Natural killer cells controlled early infection but were not essential for viral clearance. This model may provide mechanistic insights into hepatic antiviral immunity, a prerequisite for the development of HCV vaccines.

AB - An estimated 71 million people worldwide are infected with hepatitis C virus (HCV). The lack of small-animal models has impeded studies of antiviral immune mechanisms. Here we show that an HCV-related hepacivirus discovered in Norway rats can establish high-titer hepatotropic infections in laboratory mice with immunological features resembling those seen in human viral hepatitis. Whereas immune-compromised mice developed persistent infection, immune-competent mice cleared the virus within 3 to 5 weeks. Acute clearance was T cell dependent and associated with liver injury. Transient depletion of CD4+ T cells before infection resulted in chronic infection, characterized by high levels of intrahepatic regulatory T cells and expression of inhibitory molecules on intrahepatic CD8+ T cells. Natural killer cells controlled early infection but were not essential for viral clearance. This model may provide mechanistic insights into hepatic antiviral immunity, a prerequisite for the development of HCV vaccines.

U2 - 10.1126/science.aal1962

DO - 10.1126/science.aal1962

M3 - Journal article

C2 - 28706073

AN - SCOPUS:85025478531

SN - 0036-8075

VL - 357

SP - 204

EP - 208

JO - Science

JF - Science

IS - 6347

ER -