Development of a DNA vaccine designed to induce cytotoxic T lymphocyte responses to multiple conserved epitopes in HIV-1.
Epitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-gamma ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.
Wilson
Cara C
CC
University of Colorado Health Sciences Center, Denver, CO 80262, USA.
McKinney
Denise
D
Anders
Michelle
M
MaWhinney
Samantha
S
Forster
Jeri
J
Crimi
Claire
C
Southwood
Scott
S
Sette
Alessandro
A
Chesnut
Robert
R
Newman
Mark J
MJ
Livingston
Brian D
BD
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology*; D000328:Adult; D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D002461:Cell Line, Transformed; D017124:Conserved Sequence / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000302:isolation & purification; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D015791:HLA-A3 Antigen / Q000235:genetics / Q000276:immunology; D015793:HLA-B7 Antigen / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D011237:Predictive Value of Tests; D018089:Superantigens / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology*
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015791:HLA-A3 Antigen; D015793:HLA-B7 Antigen; D018089:Superantigens; D019444:Vaccines, DNA