Details

Autor(en) / Beteiligte

• Ebert, Gregor
• Preston, Simon
• Allison, Cody
• Cooney, James
• Toe, Jesse G.
• Stutz, Michael D.
• Ojaimi, Samar
• Scott, Hamish W.
• Baschuk, Nikola
• Nachbur, Ueli
• Torresi, Joseph
• Chin, Ruth
• Colledge, Danielle
• Li, Xin
• Warner, Nadia
• Revill, Peter
• Bowden, Scott
• Silke, John
• Begley, C. Glenn
• Pellegrini, Marc

Titel

Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-05, Vol.112 (18), p.5797-5802

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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.