Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis

Ebert, G; Allison, C; Preston, S; Cooney, J; Toe, JG; Stutz, MD; Ojaimi, S; Baschuk, N; Nachbur, U; Torresi, J; Silke, J; Begley, CG; Pellegrini, M

Author(s): Ebert, G; Allison, C; Preston, S; Cooney, J; Toe, JG; Stutz, MD; Ojaimi, S; Baschuk, N; Nachbur, U; Torresi, J; Silke, J; Begley, CG; Pellegrini, M;
Details: Publication Year 2015-04-20,Volume 112,Issue #18,Page 5803-8
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Journal Article
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.
Publisher: National Academy of Sciences
Research Division(s): Cell Signalling And Cell Death; Infection And Immunity
PubMed ID: 25902530
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426438/
Publisher's Version: https://doi.org/10.1073/pnas.1502400112
Open Access at Publisher's Site: http://www.pnas.org/content/112/18/5803.long
NHMRC Grants: NHMRC/637350, NHMRC/541902, NHMRC/1006592, NHMRC/1045549, NHMRC/1065626,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-05-20 09:04:08

Last Modified: 2015-05-20 09:11:55