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Scanning the HIV Genome for CD4⁺ T Cell Epitopes Restricted to HLA-DP4, the Most Prevalent HLA Class II Molecule¹

William M. Cohen^*, Sandra Pouvelle-Moratille^*, Xiao-Fei Wang^*, Sandrine Farci^*, Gaetan Munier^*, Dominique Charron, André Ménez^*, Marc Busson and Bernard Maillère^2,*

^* Protein Engineering and Research Department, Commissariat à l’Energie Atomique Saclay, Gif sur Yvette, France; and Institut National de la Sante et de la Recherche Medicale U396, Hôpital St. Louis, Paris, France

HLA-DP4 alleles are carried by 75% of individuals and are the most frequent HLA II alleles worldwide. Because we have recently characterized the peptide-binding specificity of HLA-DP4 molecules, we developed a peptide-binding prediction method to identify HLA-DP4-restricted peptides in multiple Ags. CD4⁺ T cell response plays a key role in the immune control of HIV infection, but few HIV-specific T cell epitopes with multi-individual specificity have been identified. They are mostly restricted to HLA-DR molecules, which are very polymorphic molecules. We therefore looked for HLA-DP4-restricted CD4⁺ T cell epitopes in the whole genome of HIV. Twenty-one peptides were selected from the HXB2 HIV genome based on the prediction of binding to HLA-DP4 molecules. They were submitted to HLA-DP4-binding assays. Seventeen peptides bound to the HLA-DP401 molecule, whereas 15 peptides bound to HLA-DP402. Six peptides bound very tightly to HLA-DP401 and were investigated for their capacity to induce specific CD4⁺ T cell lines in vitro using dendritic cells and CD4⁺ T cells collected from eight seronegative HLA-DP4⁺ donors. Four peptides from env and reverse transcriptase proteins induced in vitro-specific T cell lines restricted to HLA-DP4 molecules. Peptide-induced T cells recognized variants other than the HXB2 sequence and were stimulated by native Ags processed by immature dendritic cells. The reverse transcriptase peptide is present in 65% of the isolated HIV variants. To our knowledge, we describe the first HIV epitopes restricted to HLA-DP4 molecules.

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