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Journal of Virology, March 2004, p. 3162-3169, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.3162-3169.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Different Lassa Virus Strains by Alpha and Gamma Interferons and Comparison with a Less Pathogenic Arenavirus

Marcel Asper,1 Thomas Sternsdorf,2 Meike Hass,1 Christian Drosten,1 Antje Rhode,1 Herbert Schmitz,1 and Stephan Günther1*

Department of Virology, Bernhard-Nocht-Institute of Tropical Medicine, 20359 Hamburg, Germany,1 Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92186-58002

Received 22 August 2003/ Accepted 10 November 2003

The high pathogenicity of Lassa virus is assumed to involve resistance to the effects of interferon (IFN). We have analyzed the effects of alpha IFN (IFN-{alpha}), IFN-{gamma}, and tumor necrosis factor alpha (TNF-{alpha}) on replication of Lassa virus compared to the related, but less pathogenic, lymphocytic choriomeningitis virus (LCMV). Three low-passage Lassa virus strains (AV, NL, and CSF), isolated from humans with mild to fulminant Lassa fever, were tested. Lassa virus replication was inhibited by IFN-{alpha} and IFN-{gamma}, but not TNF-{alpha}, in Huh7 and Vero cells. The degree of IFN sensitivity of a Lassa virus isolate did not correlate with disease severity in human patients. Furthermore, cytokine effects observed for Lassa virus and LCMV (strains CH-5692, Armstrong, and WE) were similar. To address the mechanisms involved in the IFN effect, we used cell lines in which overexpression of IFN-stimulated proteins promyelocytic leukemia protein (PML) and Sp100 could be induced. Both proteins reside in PML bodies, a cellular target of the LCMV and Lassa virus Z proteins. Overexpression of PML or Sp100 did not affect replication of either virus. This, together with the previous finding that PML knockout facilitates LCMV replication in vitro and in vivo (M. Djavani, J. Rodas, I. S. Lukashevich, D. Horejsh, P. P. Pandolfi, K. L. Borden, and M. S. Salvato, J. Virol. 75:6204-6208, 2001; W. V. Bonilla, D. D. Pinschewer, P. Klenerman, V. Rousson, M. Gaboli, P. P. Pandolfi, R. M. Zinkernagel, M. S. Salvato, and H. Hengartner, J. Virol. 76:3810-3818, 2002), describes PML as a mediator within the antiviral pathway rather than as a direct effector protein. In conclusion, the high pathogenicity of Lassa virus compared to LCMV is probably not due to increased resistance to the effects of IFN-{alpha} or IFN-{gamma}. Both cytokines inhibit replication which is relevant for the design of antiviral strategies against Lassa fever with the aim of enhancing the IFN response.

* Corresponding author. Mailing address: Bernhard-Nocht-Institute of Tropical Medicine, Bernhard-Nocht-Str. 74, D-20359 Hamburg, Germany. Phone: (49) 40 42818 421. Fax: (49) 40 42818 378. E-mail: guenther{at}bni.uni-hamburg.de.

Journal of Virology, March 2004, p. 3162-3169, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.3162-3169.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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