Effects of Interferon-a/b on HBV Replication Determined by Viral Load

August 14, 2011

FULL TEXT:

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002159

Research Article

Effects of Interferon-á/â on HBV Replication Determined by Viral Load

Yongjun Tian, Wen-ling Chen, Jing-hsiung Ou*

Department of Molecular Microbiology and Immunology, Keck School of Medicine,

University of Southern California, Los Angeles, California, United States of

America

Abstract

Interferons á and â (IFN-á/â) are type I interferons produced by the host to

control microbial infections. However, the use of IFN-á to treat hepatitis B

virus (HBV) patients generated sustained response to only a minority of

patients. By using HBV transgenic mice as a model and by using hydrodynamic

injection to introduce HBV DNA into the mouse liver, we studied the effect of

IFN-á/â on HBV in vivo. Interestingly, our results indicated that IFN-á/â could

have opposite effects on HBV: they suppressed HBV replication when viral load

was high and enhanced HBV replication when viral load was low. IFN-á/â

apparently suppressed HBV replication via transcriptional and

post-transcriptional regulations. In contrast, IFN-á/â enhanced viral

replication by inducing the transcription factor HNF3ã and activating STAT3,

which together stimulated HBV gene expression and replication. Further studies

revealed an important role of IFN-á/â in stimulating viral growth and prolonging

viremia when viral load is low. This use of an innate immune response to enhance

its replication and persistence may represent a novel strategy that HBV uses to

enhance its growth and spread in the early stage of viral infection when the

viral level is low.

Author Summary

Hepatitis B virus (HBV) is a major human pathogen that can cause severe liver

diseases including hepatitis, liver cirrhosis and hepatocellular carcinoma.

Approximately 350 million people worldwide are chronic carriers of this virus.

Type I interferons (IFNs), which include IFN-á and IFN-â, are produced by the

host to control microbial infections. However, the use of IFN-á to treat HBV

patients has generated inconsistent results. By using mice as an animal model,

we have investigated the effect of type I IFNs on HBV replication in vivo. Our

results indicate that IFN-á/â can suppress HBV replication when viral load is

high and enhance HBV replication when viral load is low. These effects of

IFN-á/â on HBV are due in part to their abilities to regulate HBV gene

expression. Our further studies reveal an important role of IFN-á/â in

stimulating viral growth when viral load is low. This use of an innate immune

response to enhance its replication may represent a novel mechanism that HBV

uses to enhance its growth and spread in the early stage of infection when the

viral level is still low.

Citation: Tian Y, Chen W-l, Ou J-hJ (2011) Effects of Interferon-á/â on HBV

Replication Determined by Viral Load.

PLoS Pathog 7(7): e1002159. doi:10.1371/journal.ppat.1002159

Editor: M. , Nationwide Children's Hospital, United States of

America

Received: January 26, 2011; Accepted: May 25, 2011; Published: July 28, 2011

the terms of the Creative Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in any medium, provided the

original author and source are credited.

Funding: This research is supported by NIH grants CA123328 and AI083025. The

funder had no role in study design, data collection and analysis, decision to

publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests

exist.

* E-mail: jamesou@...

Introduction

Interferon-á (IFN-á) and interferon- â (IFN- â) are type I interferons, which

are produced by the host in response to viral infections to inhibit viral

replication [1]. After binding to its receptor, IFN-á/â activates the Janus

kinase (JAK) and its downstream signal transducer and activator of transcription

(STAT) and induces the expression of more than 300 IFN-stimulated genes (ISGs)

and many antiviral proteins [2], [3]. IFN-á has been used to treat viral

infections including hepatitis B virus (HBV), which chronically infects

approximately 350 million people in the world. Unfortunately, IFN- á generates

sustained virological response in only a minority of patients [4]. Little is

known why the majority of HBV patients do not respond to the IFN-á therapy.

HBV is a small DNA virus that infects liver. Its genome is only 3.2 Kb in size

and consists of four genes: the C gene codes for the viral core protein that

forms the viral capsid and a related protein termed precore protein, which is

the precursor of the secreted e antigen (HBeAg); the S gene codes for the viral

envelope proteins, also known as surface antigens (HBsAg); the P gene codes for

the viral DNA polymerase; and the X gene codes for a regulatory protein. To

understand why IFN-á generates different responses in HBV patients, we studied

the effect of IFN-á/â on HBV replication using mice as a model. Interestingly,

we found that interferons could suppress HBV replication when viral load is high

and enhance HBV replication when viral load is low. The suppression of HBV

replication by IFN-á/â apparently involves both transcriptional and

post-transcriptional regulations whereas the enhancement of HBV replication by

IFN-á/â is mediated by transcription factors HNF3ã and STAT3. This use of type I

interferons induced by its infection to enhance its replication thus represents

a novel strategy that HBV may use to stimulate its growth and spread in the

early stage of viral infection when the viral level is still low.

FULL TEXT:

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002159

August 14, 2011