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/K^btransgenic 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 A2K^btransgenic 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 A2K^btransgenic 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.