Dendritic cell vaccination induces cross-reactive cytotoxic T lymphocytes specific for wild-type and natural variant human immunodeficiency virus type 1 epitopes in HLA-A*0201/Kb transgenic mice.
Dendritic cells (DC) are highly efficient at inducing primary T cell responses. Consequently, DC are being investigated for their potential to prevent and/or treat human immunodeficiency virus type 1 (HIV-1) infection. In the current study, we examined the capacity of DC to elicit CD8+ cytotoxic T lymphocyte (CTL) reactivity against an HLA-A*0201-restricted HIV-1 reverse transcriptase (pol) epitope (residues 476-484) and two naturally occurring variants. Previous work demonstrated that the wild-type pol epitope is recognized by CTLs from HIV-1-infected individuals, whereas the variant pol epitopes are not, despite binding to HLA-A*0201. In agreement with these observations, parenteral administration of wild-type pol peptide induced HLA-A*0201-restricted CTL activity in A2Kb transgenic mice. In contrast, similar treatment with the two variant pol peptides failed to stimulate CTL reactivity, and this lack of immunogenicity correlated with reduced peptide:HLA-A*0201 complex stability. However, CTL responses were induced in A2Kb transgenic mice upon adoptive transfer of syngeneic bone marrow DC pulsed with the variant pol peptides. Furthermore, DC pulsed with the wild-type pol peptide elicited CTLs that cross-reacted with the variant pol epitopes. These results demonstrate that DC effectively expand the T cell repertoire of a given epitope to include cross-reactive T cell clonotypes. Accordingly, DC vaccination may aid in immune recognition of HIV-1 escape variants by broadening the T cell response.
Abdel-Motal
U M
UM
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Friedline
R
R
Poligone
B
B
Pogue-Caley
R R
RR
Frelinger
J A
JA
Tisch
R
R
D016915:AIDS Vaccines; D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D000939:Epitopes / Q000276:immunology; D015684:Gene Products, pol / Q000276:immunology / Q000378:metabolism; D014644:Genetic Variation; D006183:H-2 Antigens / Q000276:immunology; D015488:HIV Antigens / Q000276:immunology*; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D054302:pol Gene Products, Human Immunodeficiency Virus
D016915:AIDS Vaccines; D000939:Epitopes; D015684:Gene Products, pol; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015488:HIV Antigens; C438270:HIV pol peptide 476-484; C060467:HIV pol protein p65; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D010455:Peptides; D054302:pol Gene Products, Human Immunodeficiency Virus