Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

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http://jvi.asm.org/cgi/content/abstract/85/2/1048

Journal of Virology, January 2011, p. 1048-1057, Vol. 85, No. 2

0022-538X/11/$012.00+0 doi:10.1128/JVI.01998-10

Copyright © 2011, American Society for Microbiology. .

Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon

against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Richeng Mao,1,2 Jiming Zhang,2 Dong Jiang,1, Dawei Cai,3 M. Levy,3

Cuconati,3 M. Block,1,3 Ju-Tao Guo,1* and Haitao Guo1*

Institute for Biotechnology and Virology Research, Department of Microbiology

and Immunology, Drexel University College of Medicine, 3805 Old Easton Road,

Doylestown, Pennsylvania 18902,1 Department of Infectious Diseases, Huashan

Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040 China,2

Institute for Hepatitis and Virus Research, Hepatitis B Foundation, 3805 Old

Easton Road, Doylestown, Pennsylvania 189023

Received 20 September 2010/ Accepted 4 November 2010

Alpha interferon (IFN-) is an approved medication for chronic hepatitis B. Gamma

interferon (IFN-) is a key mediator of host innate and adaptive antiviral

immunity against hepatitis B virus (HBV) infection in vivo. In an effort to

elucidate the antiviral mechanism of these cytokines, 37 IFN-stimulated genes

(ISGs), which are highly inducible in hepatocytes, were tested for their ability

to inhibit HBV replication upon overexpression in human hepatoma cells. One ISG

candidate, indoleamine 2,3-dioxygenase (IDO), an IFN--induced enzyme catalyzing

tryptophan degradation, efficiently reduced the level of intracellular HBV DNA

without altering the steady-state level of viral RNA. Furthermore, expression of

an enzymatically inactive IDO mutant did not inhibit HBV replication, and

tryptophan supplementation in culture completely restored HBV replication in

IDO-expressing cells, indicating that the antiviral effect elicited by IDO is

mediated by tryptophan deprivation. Interestingly, IDO-mediated tryptophan

deprivation preferentially inhibited viral protein translation and genome

replication but did not significantly alter global cellular protein synthesis.

Finally, tryptophan supplementation was able to completely restore HBV

replication in IFN-- but not IFN--treated cells, which strongly argues that IDO

is the primary mediator of IFN--elicited antiviral response against HBV in human

hepatocyte-derived cells.

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* Corresponding author. Mailing address: Institute for Biotechnology and

Virology Research, Department of Microbiology and Immunology, Drexel University

College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902. Phone for

Haitao Guo: (215) 489-4928. Fax: (215) 489-4920. E-mail:

Haitao.Guo@.... Phone for Ju-Tao Guo: (215) 489-4929. Fax: (215)

489-4920. E-mail: Ju-Tao.Guo@...

Published ahead of print on 17 November 2010.

Present address: Peking University People's Hospital, Hepatology Institute, 11

Xizhimen South Street, Beijing 100044, China.