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Journal of Virology, January 2009, p. 847-858, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.02008-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Activation of Pattern Recognition Receptor-Mediated Innate Immunity Inhibits the Replication of Hepatitis B Virus in Human Hepatocyte-Derived Cells{triangledown}

Haitao Guo,1,{dagger} Dong Jiang,1,{dagger} Dongling Ma,1 Jinhong Chang,1 Anne Marie Dougherty,2 Andrea Cuconati,2 Timothy M. Block,1,2 and Ju-Tao Guo1*

Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine,1 Institute for Hepatitis and Virus Research, Hepatitis B Foundation, Doylestown, Pennsylvania 189012

Received 23 September 2008/ Accepted 14 October 2008

Recognition of virus infections by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation associated gene 5 (MDA5), activates signaling pathways, leading to the induction of inflammatory cytokines that limit viral replication. To determine the effects of PRR-mediated innate immune response on hepatitis B virus (HBV) replication, a 1.3mer HBV genome was cotransfected into HepG2 or Huh7 cells with plasmid expressing TLR adaptors, myeloid differentiation primary response gene 88 (MyD88), and TIR-domain-containing adaptor-inducing beta interferon (TRIF), or RIG-I/MDA5 adaptor, interferon promoter stimulator 1 (IPS-1). The results showed that expressing each of the three adaptors dramatically reduced the levels of HBV mRNA and DNA in both HepG2 and Huh7 cells. However, HBV replication was not significantly affected by treatment of HBV genome-transfected cells with culture media harvested from cells transfected with each of the three adaptors, indicating that the adaptor-induced antiviral response was predominantly mediated by intracellular factors rather than by secreted cytokines. Analyses of involved signaling pathways revealed that activation of NF-{kappa}B is required for all three adaptors to elicit antiviral response in both HepG2 and Huh7 cells. However, activation of interferon regulatory factor 3 is only essential for induction of antiviral response by IPS-1 in Huh7 cells, but not in HepG2 cells. Furthermore, our results suggest that besides NF-{kappa}B, additional signaling pathway(s) are required for TRIF to induce a maximum antiviral response against HBV. Knowing the molecular mechanisms by which PRR-mediated innate defense responses control HBV infections could potentially lead to the development of novel therapeutics that evoke the host cellular innate antiviral response to control HBV infections.

* Corresponding author. Mailing address: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Rd. Doylestown, PA 18902. Phone: (215) 489-4929. Fax: (215) 489-4920. E-mail: ju-tao.guo{at}drexelmed.edu

{triangledown} Published ahead of print on 29 October 2008.

{dagger} H.G. and D.J. contributed equally to this study.

Journal of Virology, January 2009, p. 847-858, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.02008-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, N., Liang, Y., Devaraj, S., Wang, J., Lemon, S. M., Li, K. (2009). Toll-Like Receptor 3 Mediates Establishment of an Antiviral State against Hepatitis C Virus in Hepatoma Cells. J. Virol. 83: 9824-9834 [Abstract] [Full Text]  


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