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.
journal_name
Proc Natl Acad Sci U S Aauthors
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 Mdoi
10.1073/pnas.1502400112subject
Has Abstractpub_date
2015-05-05 00:00:00pages
5803-8issue
18eissn
0027-8424issn
1091-6490pii
1502400112journal_volume
112pub_type
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