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Journal of Virology, September 2007, p. 9490-9501, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00364-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of a Novel Virulence Factor in Recombinant Pneumonia Virus of Mice{triangledown}

Christine D. Krempl,1,2* Anna Wnekowicz,1 Elaine W. Lamirande,2 Giw Nayebagha,1 Peter L. Collins,2 and Ursula J. Buchholz2

Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany,1 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892-80072

Received 20 February 2007/ Accepted 6 June 2007

Pneumonia virus of mice (PVM) is a murine relative of human respiratory syncytial virus (HRSV). Here we developed a reverse genetics system for PVM based on a consensus sequence for virulent strain 15. Recombinant PVM and a version engineered to express green fluorescent protein replicated as efficiently as the biological parent in vitro but were 4- and 12.5-fold attenuated in vivo, respectively. The G proteins of HRSV and PVM have been suggested to contribute to viral pathogenesis, but this had not been possible to study in a defined manner in a fully permissive host. As a first step, we evaluated recombinant mutants bearing a deletion of the entire G gene ({Delta}G) or expressing a G protein lacking its cytoplasmic tail (Gt). Both G mutants replicated as efficiently in vitro as their recombinant parent, but both were nonpathogenic in mice at doses that would otherwise be lethal. We could not detect replication of the {Delta}G mutant in mice, indicating that its attenuation is based on a severe reduction in the virus load. In contrast, the Gt mutant appeared to replicate as efficiently in mice as its recombinant parent. Thus, the reduction in virulence associated with the Gt mutant could not be accounted for by a reduction in viral replication. These results identified the cytoplasmic tail of G as a virulence factor whose effect is not mediated solely by the viral load. In addition to its intrinsic interest, a recombinant virus that replicates with wild-type-like efficiency but does not cause disease defines optimal properties for vaccine development.

* Corresponding author. Present address: Institute of Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg, Germany. Phone: (49) 931-201-49586. Fax: (49) 931-201-49553. E-mail: ckrempl{at}vim.uni-wuerzburg.de

{triangledown} Published ahead of print on 13 June 2007.

Journal of Virology, September 2007, p. 9490-9501, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00364-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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