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304 HIV-1-Specific Immunity after Genetic Immunization Is Enhanced by Modification of Gag and Pol Expression
Y. Huang*, W. Kong, and G. J. Nabel
Vaccine Res. Ctr., NIAID, NIH, Bethesda, MD, USA
Background: Protective immunity against human immunodeficiency virus-1 (HIV-1) is likely to require recognition of linear and conformation epitopes from multiple HIV antigens. Whether these responses can be elicited more effectively by virion-like structures or synthetic polyproteins is unknown. In this study, we have examined the immune response to HIV-1 Gag and Pol after plasmid DNA immunization with Rev-independent expression vectors encoding various forms of these proteins.
Methods: Immune responses were analyzed after vaccination with 4 expression vectors with modification to the codons to allow high level Rev-independent expression of HIV-1 Gag-Pol precursor proteins in human cells. These vectors include Gag alone or Gag-Pol, both of which gave rise to virion-like particles (VLPs), compared with Pol alone or a Gag-Pol fusion protein that did not form VLPs.
Results: The expression of Gag precursor proteins from these codon-altered vectors was >10-fold higher than viral Gag-Pol, and the level of accumulated Gag-Pol fusion protein was 100-fold higher in transfected cells. Overall, the Gag-Pol fusion protein induced the most broad and potent CTL responses to Gag and Pol in DNA-vaccinated mice, and this immunogen also readily elicited an antibody response to HIV-1 Gag and Pol determinants.
Conclusions: These findings suggest that the Gag-Pol fusion protein induces a broader range of CTL and antibody responses and allows delivery of an immunogen with a larger number of epitopes in a single continuous open reading frame. The data indicate that this protein represents a potentially useful component of an AIDS vaccine. Similar constructs have now been prepared for different clades, including clades A, B, C, and E.
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