An evaluation of enforced rapid proteasomal degradation as a means of enhancing vaccine-induced CTL responses.
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-gamma by CD8(+) T cells compared with mice immunized with stable forms of Gag. Production of IFN-gamma 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.
Program in Cellular and Molecular Medicine, Department of Medicine, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
S B Justin
SB
Wong
Christopher B
CB
Buck
Xuefei
X
Shen
Robert F
RF
Siliciano
D016915:AIDS Vaccines / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000276:immunology*; D005260:Female; D015683:Gene Products, gag / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D009097:Multienzyme Complexes / Q000187:drug effects / Q000276:immunology*; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010957:Plasmids / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D016915:AIDS Vaccines; D015683:Gene Products, gag; D009097:Multienzyme Complexes; D010455:Peptides; D011498:Protein Precursors; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex