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 Li; Nadia Warner; Peter Revill; Scott Bowden; John Silke; C. Glenn Begley; Marc Pellegrini

doi:10.1073/pnas.1502390112

New Research In

Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, and approved March 24, 2015 (received for review February 4, 2015)

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Significance

Hepatitis B virus (HBV) causes substantial morbidity and mortality. A large proportion of infected individuals controls infection but does not completely eradicate HBV DNA from the liver, and flares in hepatitis can be precipitated by immunosuppression. A proportion of individuals never controls infection, and these people are at substantial risk of developing liver failure and liver cancer. Current therapies are not effective at eliminating virus, and there is a major interest in developing functional cures for HBV infection. We identified host cell signaling molecules that can restrict the ability to eradicate infected cells. These molecules can be therapeutically targeted, and drugs that interfere with the function of these host cell proteins may be useful therapies to promote clearance of HBV infection.

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.

Footnotes

↵¹S.P. and C.A. contributed equally to this work.
↵²To whom correspondence should be addressed. Email: pellegrini{at}wehi.edu.au.

Author contributions: G.E., S.P., C.A., J.C., J.G.T., M.D.S., S.O., H.W.S., N.B., U.N., J.T., R.C., D.C., X.L., N.W., P.R., S.B., J.S., C.G.B., and M.P. designed research; G.E., S.P., C.A., J.C., J.G.T., M.D.S., S.O., H.W.S., N.B., U.N., R.C., D.C., X.L., and N.W. performed research; G.E., S.P., C.A., J.C., J.G.T., M.D.S., S.O., H.W.S., N.B., U.N., J.T., R.C., D.C., X.L., N.W., P.R., S.B., J.S., C.G.B., and M.P. analyzed data; and G.E. and M.P. wrote the paper.
Conflict of interest statement: The Walter and Eliza Hall Institute of Medical Research has a research license agreement with TetraLogic Pharmaceuticals Corporation, Inc., the manufacturer of the cellular inhibitor of apoptosis protein antagonist birinapant. TetraLogic Pharmaceuticals Corporation, Inc. has filed a patent cooperation treaty application on behalf of The Walter and Eliza Hall Institute of Medical Research. J.S. is on the scientific advisory board of and M.P. provides consultative advice to TetraLogic Pharmaceuticals Corporation, Inc. J.S. has options on a small number of shares in TetraLogic Pharmaceuticals Corporation, Inc. C.G.B is employed by TetraLogic Pharmaceuticals Corporation, Inc.
This article is a PNAS Direct Submission.
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