Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus
Gregor Ebert, Simon Preston, Cody Allison, James Cooney, Jesse G Toe, Michael D Stutz, Samar Ojaimi, Hamish W Scott, Nikola Baschuk, Ueli Nachbur, Joseph Torresi, Ruth Chin, Danielle Colledge, Xin Lie, Nadia Warner, Peter Revill, Scott Bowden, John Silke, C Glenn Begley, Marc Pellegrini
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2015
Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control ..View full abstract
Awarded by National Health and Medical Research Council Australia Career Development Award
We thank Stephen Condon and Stephen Locarnini for discussions. Pei-Jer Chen and Ding-Shinn Chen constructed the hepatitis B virus infection vector for hydrodynamic injection. David Vaux generated the cellular inhibitor of apoptosis protein 1<SUP>loxP/loxP</SUP> (cIAP1<SUP>loxP/loxP</SUP>) and cIAP2<SUP>FRT/lFRT</SUP> mice. Paul Hertzog provided reagents, and Lynne Waddington assisted with EM. Linda Earnest-Silveira provided laboratory support. The following mouse strain was obtained through National Institute of Allergy and Infectious Diseases Exchange Program 04215 C57BL/6-H-2Kb-H-2Db. This work was supported by Australian Research Council Future Fellowship Award (to U.N.) and Grant FT1301000166; National Health and Medical Research Council Australia Career Development Award 637350 and Grants 541901 (to J.S.), 541902 (to J.S.), 1006592 (to M.P.), 1045549 (to M.P.), and 1065626 (to M.P.); the Victorian State Government Operational Infrastructure Support; and the Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council.