Expansion after epitope peptide exposure in vitro predicts cytotoxic T lymphocyte epitope dominance hierarchy in lymphocytes of vaccinated mamu-a*01+ rhesus monkeys.
Because of the importance of developing HIV vaccine strategies that generate cytotoxic T lymphocyte (CTL) responses with a maximal breadth of epitope recognition, we have explored a variety of novel strategies designed to overcome the usual propensity of CTLs to focus recognition on a limited number of dominant epitopes. In studies of rhesus monkeys expressing the Mamu-A*01 MHC class I allele, we show that variously configured multiepitope plasmid DNA vaccine constructs elicit CTL populations that do not evidence skewing of recognition to dominant epitopes. Nevertheless, repeated boosting of these vaccinated monkeys with different live recombinant vaccine vectors uncovers and amplifies the usual CTL epitope dominance hierarchy. Importantly, in vitro peptide stimulation of peripheral blood mononuclear cells from monkeys that have received only a multiepitope plasmid DNA priming immunization uncovers this dominance hierarchy. Therefore, the dominance hierarchy of the vaccine-elicited epitope-specific CTL populations is inherent in the T lymphocytes of the monkeys after initial exposure to epitope peptides, and the ultimate breadth of epitope recognition cannot be modified thereafter. This finding underscores the enormous challenge associated with increasing the breadth of CTL recognition through vaccination.
Subbramanian
Ramu A
RA
Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Charini
William A
WA
Kuroda
Marcelo J
MJ
Seaman
Michael
M
Chhay
Heng
H
Lifton
Michelle A
MA
Gorgone
Darci A
DA
Schmitz
Jörn E
JE
Carville
Angela
A
Letvin
Norman L
NL
D000483:Alleles; D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology*; D066298:In Vitro Techniques; D008253:Macaca mulatta; D010455:Peptides / Q000276:immunology; D010957:Plasmids / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; C110764:Mamu-A 01 antigen; D010455:Peptides; D019444:Vaccines, DNA