CTLS FROM LYMPHOID ORGANS RECOGNIZE AN OPTIMAL HLA-A2-RESTRICTED AND HLA-B52-RESTRICTED NONAPEPTIDE AND SEVERAL EPITOPES IN THE C-TERMINAL REGION OF HIV-1 NEF

In a previous analysis of HIV-1-specific CTLs in lymphoid organs from HIV-seropositive patients, we reported high frequencies of in vivo dif ferentiated CTLs directed against two immunodominant regions in the ce ntral and in the C-terminal part of the HIV-1 Nef protein. The present study analyzes the epitopes recognized by CTLs in the carboxyl termin us of Nef (amino acids 182-205). In addition to several epitopes that are recognized in association with different HLA molecules (A1, A2, A2 5(10), B35, B52), we defined an optimal nonapeptide (190-198). This no napeptide was recognized by CTLs down to nanomolar concentrations in t he context of at least two HLA molecules, HLA-B52 and HLA-A2, includin g three HLA-A2 subtypes: HLA-A2.1, -A2.2, and -A2.4. We also determine d the relative frequencies of effector CTLs directed against peptide 1 90-198 to be as high as 10(-4), as opposed to lower frequencies rangin g between 5 x 10(-5) and 5 x 10(-6) observed for the other peptides re cognized in the same region, thus confirming the optimal presentation of this nonapeptide in vivo. Molecular modeling of the interactions be tween HLA-A2.1 and Nef peptide 190-198 suggests the formation of a sta ble complex and allowed us to study sequence motifs that are important for the binding of the HIV-1 peptide in the pockets of the HLA-A2.1 m olecule.