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Journal of Virology, January 2008, p. 207-219, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01515-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Attenuation of Recombinant Vesicular Stomatitis Virus-Human Immunodeficiency Virus Type 1 Vaccine Vectors by Gene Translocations and G Gene Truncation Reduces Neurovirulence and Enhances Immunogenicity in Mice{triangledown}

David Cooper,* Kevin J. Wright, Priscilla C. Calderon, Min Guo, Farooq Nasar, J. Erik Johnson, John W. Coleman, Margaret Lee, Cheryl Kotash, Irene Yurgelonis, Robert J. Natuk, R. Michael Hendry, Stephen A. Udem,{dagger} and David K. Clarke

Wyeth Vaccines Research, Wyeth, 401 N. Middletown Rd., Pearl River, New York 10965

Received 10 July 2007/ Accepted 7 October 2007

Recombinant vesicular stomatitis virus (rVSV) has shown great potential as a new viral vector for vaccination. However, the prototypic rVSV vector described previously was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates. Here, we describe the attenuation, neurovirulence, and immunogenicity of rVSV vectors expressing human immunodeficiency virus type 1 Gag. These rVSV vectors were attenuated by combinations of the following manipulations: N gene translocations (N4), G gene truncations (CT1 or CT9), noncytopathic M gene mutations (Mncp), and positioning of the gag gene into the first position of the viral genome (gag1). The resulting N4CT1-gag1, N4CT9-gag1, and MncpCT1-gag1 vectors demonstrated dramatically reduced neurovirulence in mice following direct intracranial inoculation. Surprisingly, in spite of a very high level of attenuation, the N4CT1-gag1 and N4CT9-gag1 vectors generated robust Gag-specific immune responses following intramuscular immunization that were equivalent to or greater than immune responses generated by the more virulent prototypic vectors. MncpCT1-gag1 also induced Gag-specific immune responses following intramuscular immunization that were equivalent to immune responses generated by the prototypic rVSV vector. Placement of the gag gene in the first position of the VSV genome was associated with increased in vitro expression of Gag protein, in vivo expression of Gag mRNA, and enhanced immunogenicity of the vector. These findings demonstrate that through directed manipulation of the rVSV genome, vectors that have reduced neurovirulence and enhanced immunogenicity can be made.

* Corresponding author. Mailing address: Wyeth, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-7991. Fax: (845) 602-4941. E-mail: cooperd3{at}wyeth.com

{triangledown} Published ahead of print on 17 October 2007.

{dagger} Present address: IAVI, 110 William St., Floor 27, New York, NY 10038.

Journal of Virology, January 2008, p. 207-219, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01515-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Xu, R., Nasar, F., Megati, S., Luckay, A., Lee, M., Udem, S. A., Eldridge, J. H., Egan, M. A., Emini, E., Clarke, D. K. (2009). Prime-Boost Vaccination with Recombinant Mumps Virus and Recombinant Vesicular Stomatitis Virus Vectors Elicits an Enhanced Human Immunodeficiency Virus Type 1 Gag-Specific Cellular Immune Response in Rhesus Macaques. J. Virol. 83: 9813-9823 [Abstract] [Full Text]  
  • Ahmed, M., Marino, T. R., Puckett, S., Kock, N. D., Lyles, D. S. (2008). Immune Response in the Absence of Neurovirulence in Mice Infected with M Protein Mutant Vesicular Stomatitis Virus. J. Virol. 82: 9273-9277 [Abstract] [Full Text]  


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