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-b transgenic mice

Dendritic cells (DC) are highly efficient at inducing primary T cell respon ses. 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 rec ognized by CTLs from HIV-1-infected individuals, whereas the variant pol ep itopes are not, despite binding to HLA-A*0201. In agreement with these obse rvations, parenteral administration of wild-type pol peptide induced HLA-A* 0201-restricted CTL activity in A2K(b) transgenic mice. In contrast, simila r treatment with the two variant pol peptides failed to stimulate CTL react ivity, and this lack of immunogenicity correlated with reduced peptide:HLA- A*0201 complex stability. However, CTL responses were induced in A2K(b) tra nsgenic mice upon adoptive transfer of syngeneic bone marrow DC pulsed with the variant pol peptides. Furthermore, DC pulsed with the wild-type pol pe ptide 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 broad ening the T cell response. (C) 2001 Academic Press.