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Journal of Virology, November 2009, p. 11330-11340, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00763-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Identification of Amino Acid Residues Critical for the Anti-Interferon Activity of the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus {triangledown}

Luis Martínez-Sobrido ,1,2,{dagger},{ddagger} Sébastien Emonet,4,{ddagger} Panagiotis Giannakas,1 Beatrice Cubitt,4 Adolfo García-Sastre,1,2,3 and Juan C. de la Torre4*

Department of Microbiology,1 Global Health and Emerging Pathogens Institute,2 Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029,3 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 920374

Received 14 April 2009/ Accepted 17 August 2009

Lymphocytic choriomeningitis virus (LCVM) nucleoprotein (NP) counteracts the host type I interferon (IFN) response by inhibiting activation of the IFN regulatory factor 3 (IRF3). In this study, we have mapped the regions and specific amino acid residues within NP involved in its anti-IFN activity. We identified a region spanning residues 382 to 386 as playing a critical role in the IFN-counteracting activity of NP. Alanine substitutions at several positions within this region resulted in NP mutants that lacked the IFN-counteracting activity but retained their functions in virus RNA synthesis and assembly of infectious particles. We used reverse genetics to rescue a recombinant LCMV strain carrying mutation D382A in its NP [rLCMV/NP*(D382A)]. Compared to wild-type (WT) LCMV, rLCMV/NP*(D382A) exhibited a higher level of attenuation in IFN-competent than IFN-deficient cells. In addition, A549 cells infected with rLCMV/NP*(D382A), but not with WT LCMV, produced IFN and failed to rescue replication of the IFN-sensitive Newcastle disease virus.

* Corresponding author. Mailing address: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037. Phone: (858) 784-9462. Fax: (858) 784-9981. E-mail: juanct{at}scripps.edu

{triangledown} Published ahead of print on 26 August 2009.

{dagger} Present address: Department of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642.

{ddagger} L.M.-S. and S.E. contributed equally to this work.

Journal of Virology, November 2009, p. 11330-11340, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00763-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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