Dominance of a nonpathogenic glycoprotein gene over a pathogenic glycoprotein gene in rabies virus.

Authors

• Milosz Faber
• Marie-Luise Faber
• Jianwei Li
• Mirjam A R Preuss
• Matthias J Schnell
• Bernhard Dietzschold

Publication/Presentation Date

7-1-2007

Abstract

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.

Volume

81

Issue

13

First Page

7041

Last Page

7047

ISSN

0022-538X

Published In/Presented At

Faber, M., Faber, M. L., Li, J., Preuss, M. A., Schnell, M. J., & Dietzschold, B. (2007). Dominance of a nonpathogenic glycoprotein gene over a pathogenic glycoprotein gene in rabies virus. Journal of virology, 81(13), 7041–7047. https://doi.org/10.1128/JVI.00357-07

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

17459937

Department(s)

Administration and Leadership

Document Type

Article