title: Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus.
abstract: 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 HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Gregor
authors.initials: G
authors.lastname: Ebert
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Simon
authors.initials: S
authors.lastname: Preston
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Cody
authors.initials: C
authors.lastname: Allison
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
authors.forename: James
authors.initials: J
authors.lastname: Cooney
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Jesse G
authors.initials: JG
authors.lastname: Toe
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Stutz
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Samar
authors.initials: S
authors.lastname: Ojaimi
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
authors.forename: Hamish W
authors.initials: HW
authors.lastname: Scott
authors.affiliation: Faculty of Science Technology and Engineering, School of Molecular Sciences, Department of Biochemistry, LaTrobe Institute for Molecular Science, Bundoora, VIC 3086, Australia;
authors.forename: Nikola
authors.initials: N
authors.lastname: Baschuk
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.affiliation: Department of Infectious Diseases and Department of Medicine, Austin Hospital, The University of Melbourne, Heidelberg, VIC 3084, Australia;
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
authors.affiliation: Department of Infectious Diseases and Department of Medicine, Austin Hospital, The University of Melbourne, Heidelberg, VIC 3084, Australia;
authors.forename: Ruth
authors.initials: R
authors.lastname: Chin
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Melbourne, VIC 3000, Australia; and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Colledge
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Melbourne, VIC 3000, Australia; and.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Melbourne, VIC 3000, Australia; and.
authors.forename: Nadia
authors.initials: N
authors.lastname: Warner
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Melbourne, VIC 3000, Australia; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Revill
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Melbourne, VIC 3000, Australia; and.
authors.forename: Scott
authors.initials: S
authors.lastname: Bowden
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.affiliation: Research and Development Division, TetraLogic Pharmaceuticals Corporation, Inc., Malvern, PA 19355.
authors.forename: C Glenn
authors.initials: CG
authors.lastname: Begley
authors.affiliation: Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; pellegrini@wehi.edu.au.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
mesh_terms: D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D005838:Genotype; D006509:Hepatitis B / Q000378:metabolism*; D006515:Hepatitis B virus; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D004279:DNA, Viral; D051034:Inhibitor of Apoptosis Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: TNF; cIAP1; cIAP2; cellular inhibitor of apoptosis proteins; hepatitis B virus