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 differentiated CTLs directed against two immunodominant regions in the central and in the C-terminal part of the HIV-1 Nef protein. The present study analyzes the epitopes recognized by CTLs in the carboxyl terminus of Nef (amino acids 182-205). In addition to several epitopes that are recognized in association with different HLA molecules (A1, A2, A25(10), B35, B52), we defined an optimal nonapeptide (190-198). This nonapeptide was recognized by CTLs down to nanomolar concentrations in the context of at least two HLA molecules, HLA-B52 and HLA-A2, including three HLA-A2 subtypes: HLA-A2.1, -A2.2, and -A2.4. We also determined the relative frequencies of effector CTLs directed against peptide 190-198 to be as high as 10(-4), as opposed to lower frequencies ranging between 5 x 10(-5) and 5 x 10(-6) observed for the other peptides recognized in the same region, thus confirming the optimal presentation of this nonapeptide in vivo. Molecular modeling of the interactions between HLA-A2.1 and Nef peptide 190-198 suggests the formation of a stable 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 molecule.
Hadida
F
F
Laboratory for Cellular and Tissue Immunology, University Hospital Center Pitié-Salpétrière, Paris, France.
Haas
G
G
Zimmermann
N
N
Hosmalin
A
A
Spohn
R
R
Samri
A
A
Jung
G
G
Debre
P
P
Autran
B
B
D001483:Base Sequence; D003198:Computer Simulation; D003602:Cytotoxicity, Immunologic; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry; D015693:Gene Products, nef / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D059950:HLA-B52 Antigen; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D008198:Lymph Nodes / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus
D000939:Epitopes; D015693:Gene Products, nef; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; D059950:HLA-B52 Antigen; D054311:nef Gene Products, Human Immunodeficiency Virus