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Journal of Virology, October 2008, p. 9730-9738, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00889-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

PPEY Motif within the Rabies Virus (RV) Matrix Protein Is Essential for Efficient Virion Release and RV Pathogenicity {triangledown}

Christoph Wirblich,1,2 Gene S. Tan,1 Amy Papaneri,1,2 Peter J. Godlewski,3 Jan Marc Orenstein,4 Ronald N. Harty,3* and Matthias J. Schnell1,2*

Department of Microbiology and Immunology,1 Jefferson Vaccine Center, Thomas Jefferson University, Philadelphia, Pennsylvania,2 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,3 Department of Pathology, George Washington University, Washington, DC4

Received 28 April 2008/ Accepted 15 July 2008

Late (L) domains containing the highly conserved sequence PPXY were first described for retroviruses, and later research confirmed their conservation and importance for efficient budding of several negative-stranded RNA viruses. Rabies virus (RV), a member of the Rhabdoviridae family, contains the sequence PPEY (amino acids 35 to 38) within the N terminus of the matrix (M) protein, but the functions of this potential L-domain in the viral life cycle, viral pathogenicity, and immunogenicity have not been established. Here we constructed a series of recombinant RVs containing mutations within the PPEY motif and analyzed their effects on viral replication and RV pathogenicity. Our results indicate that the first proline at position 35 is the most important for viral replication, whereas P36 and Y38 have a lesser but still noticeable impact. The reduction in viral replication was most likely due to inhibition of virion release, because initially no major impact on RV RNA synthesis was observed. In addition, results from electron microscopy demonstrated that the M4A mutant virus (PPEY->SAEA) displayed a more cell-associated phenotype than that of wild-type RV. Furthermore, all mutations within the PPEY motif resulted in reduced spread of the recombinant RVs as indicated by a reduction in focus size. Importantly, recombinant PPEY L-domain mutants were highly attenuated in mice yet still elicited potent antibody responses against RV G protein that were as high as those observed after infection with wild-type virus. Our data indicate that the RV PPEY motif has L-domain activity essential for efficient virus production and pathogenicity but is not essential for immunogenicity and thus can be targeted to increase the safety of rabies vaccine vectors.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Thomas Jefferson University, 531 BLSB, 233 South 10th St., Philadelphia, PA 19107. Phone: (215) 503-4634. Fax: (215) 503-5393. E-mail for M. Schnell: Matthias.schnell{at}jefferson.edu. E-mail for R. Harty: rharty{at}vet.upenn.edu

{triangledown} Published ahead of print on 30 July 2008.

Journal of Virology, October 2008, p. 9730-9738, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00889-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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