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Journal of Virology, January 2003, p. 237-244, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.237-244.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Second-Generation Rabies Virus-Based Vaccine Vectors Expressing Human Immunodeficiency Virus Type 1 Gag Have Greatly Reduced Pathogenicity but Are Highly Immunogenic

James P. McGettigan,1,2 Roger J. Pomerantz,1,2,3 Catherine A. Siler,1,2 Philip M. McKenna,1,4 Heather D. Foley,1,4 B. Dietzschold,1,4 and Matthias J. Schnell1,2*

The Dorrance H. Hamilton Laboratories, Center for Human Virology,1 Departments of Biochemistry and Molecular Pharmacology,2 Medicine,3 Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 191074

Received 25 June 2002/ Accepted 20 September 2002

Rabies virus (RV) vaccine strain-based vectors show great promise as vaccines against other viral diseases such as human immunodeficiency virus type 1 (HIV-1) infection and hepatitis C, but a low residual pathogenicity remains a concern for their use. Here we describe several highly attenuated second-generation RV-based vaccine vehicles expressing HIV-1 Gag. For this approach, we modified the previously described RV vaccine vector SPBN by replacing the arginine at position 333 (R333) within the RV glycoprotein (G) with glutamic acid (E333), deleting 43 amino acids of the RV G cytoplasmic domain (CD), or combining the R333 exchange and the CD deletion. In addition, we constructed a new RV vector that expresses HIV-1 Gag from an RV transcription unit upstream of the RV phosphoprotein gene (BNSP-Gag) instead of upstream of the G gene. As expected and as demonstrated for SPBN-Gag, all vaccine vehicles were apathogenic after peripheral administration. However, the new, second-generation vaccine vectors containing modifications in the RV G were also apathogenic after intracranial infection with 105 infectious particles, and BNSP-Gag produced a 50%-reduced mortality in mice. Of note, the observed attenuation of pathogenicity did not result in either the attenuation of the humoral response against the RV G or the previously observed robust cellular response against HIV-1 Gag. These findings demonstrate that very safe and highly effective RV-based vaccines can be constructed and further emphasize their potential utility as efficacious antiviral vaccines.

* Corresponding author. Mailing address: 1020 Locust St., Suite 335, Philadelphia, PA 19107-6799. Phone: (215) 503-1260. Fax: (215) 923-1956. E-mail: matthias.schnell{at}mail.tju.edu.

Journal of Virology, January 2003, p. 237-244, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.237-244.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Koser, M. L., McGettigan, J. P., Tan, G. S., Smith, M. E., Koprowski, H., Dietzschold, B., Schnell, M. J. (2004). Rabies virus nucleoprotein as a carrier for foreign antigens. Proc. Natl. Acad. Sci. USA 101: 9405-9410 [Abstract] [Full Text]  


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