title: Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis.
abstract: We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4(+) T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.
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: 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; 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;
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: 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; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
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; D000998:Antiviral Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D004279:DNA, Viral / Q000097:blood; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006509:Hepatitis B / Q000188:drug therapy* / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D016130:Immunophenotyping; D007211:Indoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D010957:Plasmids / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D004151:Dipeptides; D006514:Hepatitis B Surface Antigens; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; C413685:entecavir; D006147:Guanine; C582429:birinapant
keywords: Smac mimetic; TNF; birinapant; cellular inhibitor of apoptosis proteins; hepatitis B virus