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Journal of Virology, March 2001, p. 2684-2691, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2684-2691.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibition of Hepatitis B Virus Replication by the Interferon-Inducible MxA Protein

Emmanuel Gordien, Olivier Rosmorduc,dagger Cécile Peltekian, Florianne Garreau, Christian Bréchot, and Dina Kremsdorf*

INSERM U370, Institut Necker, Paris, France

Received 28 June 2000/Accepted 11 December 2000

Human MxA is an alpha/beta interferon-inducible intracytoplasmic protein that mediates antiviral activity against several RNA viruses. We had previously shown that overexpression of the hepatitis B virus (HBV) capsid led to selective downregulation of MxA gene expression, suggesting a mechanism by which the virus escapes from the host defense system (O. Rosmorduc, H. Sirma, P. Soussan, E. Gordien, P. Lebon, M. Horisberger, C. Brechot and D. Kremsdorf, J. Gen. Virol. 80:1253-1262, 1999). In the present study, we investigated the antiviral activity of MxA protein against HBV. MxA-expressing HuH7 clones were established and transiently transfected with HBV, and viral replication was then studied. Viral protein secretion was profoundly reduced in MxA-expressing clones by 80% for HBV surface antigen (HBsAg) and 70% for HBV e antigen (HBeAg). The levels of intracytoplasmic HBsAg and HBeAg were reduced by about 80 and 50% in the two MxA-positive clones tested. A nearly complete disappearance of HBV DNA replicative intermediates was observed in MxA-expressing clones. Although the expression of total viral RNAs was not modified, two- to fourfold reductions in HBV cytoplasmic RNAs were found in MxA-expressing clones. This suggests the inhibition of HBV replication at a posttranscriptional level. Indeed, using the well-characterized posttranscriptional regulation element (PRE) reporter system, we were able to demonstrate a marked reduction (three- to eightfold) in the nucleocytoplasmic export of unspliced RNA in MxA-expressing clones. In addition, MxA protein did not interact with HBV nucleocapsid or interfere with HBV nucleocapsid formation. Our results show an antiviral effect of MxA protein on a DNA virus for the first time. MxA protein acts, at least in part, by inhibiting the nucleocytoplasmic export of viral mRNA via the PRE sequence.

* Corresponding author. Mailing address: INSERM U370, Faculté de Médecine Necker Enfants-Malades, 156 rue de Vaugirard, 75015 Paris, France. Phone: (33) (1) 40 61 56 40. Fax: (33) (1) 40 61 55 81. E-mail: kremsdor{at}necker.fr.

dagger Present address: Service d'Hépatologie, C.H.U. Saint-Antoine, Paris, France.

Journal of Virology, March 2001, p. 2684-2691, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2684-2691.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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