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An Evaluation of Enforced Rapid Proteasomal Degradation as a Means of Enhancing Vaccine-Induced CTL Responses¹

S. B. Justin Wong^2,*, Christopher B. Buck^2,*, Xuefei Shen^2, and Robert F. Siliciano^3,

^* Program in Cellular and Molecular Medicine, Program in Biochemistry, Cellular and Molecular Biology, Graduate Program in Immunology, Department of Medicine, and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205

The HIV-1 Gag protein is an attractive target for CTL-based vaccine strategies because it shows less sequence variability than other HIV-1 proteins. In an attempt to increase the immunogenicity of HIV-1 Gag, we created Gag variants that were targeted to the proteasomal pathway for rapid degradation. This enhanced rate of degradation was associated with increased presentation of MHC class I-associated antigenic peptides on the cell surface. Despite this, immunizing mice with either plasmid DNA or recombinant vaccinia vectors expressing unstable Gag failed to produce significant increases in bulk CTL responses or Ag-specific production of IFN- by CD8⁺ T cells compared with mice immunized with stable forms of Gag. Production of IFN- by CD4⁺ T cells was also impaired, and we speculate that the abrogation of CD4⁺ T cell help was responsible for the impaired CTL response. These results suggest that vaccine strategies designed to increase the density of peptide-MHC class I complexes on the surfaces of APC may not necessarily enhance immunogenicity with respect to CTL responses.

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