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Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis

Gregor Ebert1, Cody Allison1, Simon Preston1

  • 1Division 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;

Proceedings of the National Academy of Sciences of the United States of America
|April 23, 2015
PubMed

Insights

Smac mimetics, like birinapant, effectively reduce hepatitis B virus (HBV) DNA and antigens in mice. These drugs promote the clearance of infected cells, offering a potential new therapy for chronic HBV infection.

Area of Science:

  • Hepatology
  • Immunology
  • Pharmacology

Background:

  • Cellular inhibitor of apoptosis proteins (cIAPs) hinder the clearance of hepatitis B virus (HBV) by blocking TNF-mediated cell death.
  • Developing therapies to eliminate infected cells is crucial for treating chronic HBV.

Purpose of the Study:

  • To investigate the therapeutic potential of Smac mimetics, which inhibit cIAPs, in a mouse model of chronic HBV infection.
  • To determine if Smac mimetics can promote the elimination of HBV-infected hepatocytes.

Main Methods:

  • Utilized an immunocompetent mouse model of chronic HBV infection.
  • Administered Smac mimetics, including birinapant, and assessed their impact on viral markers and infected cells.
  • Evaluated the role of host CD4(+) T cells and TNF in Smac mimetic efficacy.

Main Results:

  • Birinapant and other Smac mimetics rapidly decreased serum HBV DNA and HBV surface antigen levels.
  • Smac mimetics promoted the elimination of hepatocytes expressing HBV core antigen.
  • The efficacy of Smac mimetics was contingent upon their chemical properties, host CD4(+) T cells, and TNF signaling.
  • Birinapant potentiated the antiviral effects of entecavir in reducing viral DNA production.

Conclusions:

  • Smac mimetics, such as birinapant, demonstrate significant potential as a novel therapeutic strategy for treating chronic HBV infection.
  • These findings suggest that Smac mimetics may also be effective against other intracellular infections.
Keywords:
Smac mimeticTNFbirinapantcellular inhibitor of apoptosis proteinshepatitis B virus

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