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Journal of Virology, July 2007, p. 7041-7047, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00357-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Dominance of a Nonpathogenic Glycoprotein Gene over a Pathogenic Glycoprotein Gene in Rabies Virus{triangledown}

Milosz Faber,1 Marie-Luise Faber,2 Jianwei Li,1 Mirjam A. R. Preuss,1 Matthias J. Schnell,1 and Bernhard Dietzschold1*

Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,1 Molecular Targeting Technologies, 882 S. Matlack St., Suite 105, West Chester, Pennsylvania 193822

Received 19 February 2007/ Accepted 12 April 2007

The nonpathogenic phenotype of the live rabies virus (RV) vaccine SPBNGAN is determined by an Arg->Glu exchange at position 333 in the glycoprotein, designated GAN. We recently showed that after several passages of SPBNGAN in mice, an Asn->Lys mutation arose at position 194 of GAN, resulting in GAK, which was associated with a reversion to the pathogenic phenotype. Because an RV vaccine candidate containing two GAN genes (SPBNGAN-GAN) exhibits increased immunogenicity in vivo compared to the single-GAN construct, we tested whether the presence of two GAN genes might also enhance the probability of reversion to pathogenicity. Comparison of SPBNGAN-GAN with RVs constructed to contain either both GAN and GAK genes (SPBNGAN-GAK and SPBNGAK-GAN) or two GAK genes (SPBNGAK-GAK) showed that while SPBNGAK-GAK was pathogenic, SPBNGAN-GAN and SPBNGAN-GAK were completely nonpathogenic and SPBNGAK-GAN showed strongly reduced pathogenicity. Analysis of genomic RV RNA in mouse brain tissue revealed significantly lower virus loads in SPBNGAN-GAK- and SPBNGAK-GAN-infected brains than those detected in SPBNGAK-GAK-infected brains, indicating the dominance of the nonpathogenic phenotype determined by GAN over the GAK-associated pathogenic phenotype. Virus production and viral RNA synthesis were markedly higher in SPBNGAN-, SPBNGAK-GAN-, and SPBNGAN-GAK-infected neuroblastoma cells than in the SPBNGAK- and SPBNGAK-GAK-infected counterparts, suggesting control of GAN dominance at the level of viral RNA synthesis. These data point to the lower risk of reversion to pathogenicity of a recombinant RV carrying two identical GAN genes compared to that of an RV carrying only a single GAN gene.

* Corresponding author. Mailing address: 233 South 10th Street, BLSB 533, Philadelphia, PA 19107-5541. Phone: (215) 503-4692. Fax: (215) 503-5393. E-mail: bernhard.dietzschold{at}jefferson.edu

{triangledown} Published ahead of print on 25 April 2007.

Journal of Virology, July 2007, p. 7041-7047, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00357-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Faber, M., Li, J., Kean, R. B., Hooper, D. C., Alugupalli, K. R., Dietzschold, B. (2009). Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus. Proc. Natl. Acad. Sci. USA 106: 11300-11305 [Abstract] [Full Text]  
  • Pulmanausahakul, R., Li, J., Schnell, M. J., Dietzschold, B. (2008). The Glycoprotein and the Matrix Protein of Rabies Virus Affect Pathogenicity by Regulating Viral Replication and Facilitating Cell-to-Cell Spread. J. Virol. 82: 2330-2338 [Abstract] [Full Text]  


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