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Journal of Virology, January 2009, p. 584-597, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01443-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Optimization of Human Immunodeficiency Virus Gag Expression by Newcastle Disease Virus Vectors for the Induction of Potent Immune Responses {triangledown}

Elena Carnero,1,§ Wenjing Li,1,§ Antonio V. Borderia,1 Bruno Moltedo,1 Thomas Moran,1 and Adolfo García-Sastre1,2,3*

Department of Microbiology,1 Department of Medicine,2 Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 100293

Received 10 July 2008/ Accepted 24 October 2008

One attractive strategy for the development of a human immunodeficiency virus (HIV) vaccine is the use of viral vectors with a proven safety profile and an absence of preexisting immunity in humans, such as Newcastle disease virus (NDV). Several NDV vaccine vectors have been generated, and their immunogenicities have been investigated with different animal models. However, a systematic study to evaluate the optimal insertion site of the foreign antigens into NDV that results in enhanced immune responses specific to the antigen has not yet been conducted. In this article, we describe the ability of NDV expressing HIV Gag to generate a Gag-specific immune response in mice. We also have determined the optimal insertion site into the NDV genome by generating recombinant NDV-HIVGag viruses in which HIV gag was located at different transcriptional positions throughout the NDV viral genome. All recombinant viruses were viable, grew to similar titers in embryonated chicken eggs, and expressed Gag in a stable manner. Our in vivo experiments revealed that higher HIV Gag protein expression positively correlates with an enhanced CD8+ T-cell-mediated immune response and protective immunity against challenge with vaccinia virus expressing HIV Gag. We also inserted a codon-optimized version of HIV gag in the described best location, between the P and M genes. Virus expressing the codon-optimized version of HIV gag induced a higher expression of the protein and an enhanced immune response against HIV Gag in mice. These results indicate that strategies directed toward increasing antigen expression by NDV result in enhanced immunogenicity and vaccine efficacy.

* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1124, New York, NY 10029. Phone: (212) 241-7769. Fax: (212) 534-1684. E-mail: adolfo.garcia-sastre{at}mssm.edu

{triangledown} Published ahead of print on 12 November 2008.

§ These authors contributed equally to this work.

Journal of Virology, January 2009, p. 584-597, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01443-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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