A long N-terminal-extended nested set of abundant and antigenic major histocompatibility complex class I natural ligands from HIV envelope protein.
Viral antigens complexed with major histocompatibility complex (MHC) class I molecules are recognized by cytotoxic T lymphocytes on infected cells. Assays with synthetic peptides identify optimal MHC class I ligands often used for vaccines. However, when natural peptides are analyzed, more complex mixtures including long peptides bulging in the middle of the binding site or with carboxyl extensions are found, reflecting lack of exposure to carboxypeptidases in the antigen processing pathway. In contrast, precursor peptides are exposed to extensive cytosolic aminopeptidase activity, and fewer than 1% survive, only to be further trimmed in the endoplasmic reticulum. We show here a striking example of a nested set of at least three highly antigenic and similarly abundant natural MHC class I ligands, 15, 10, and 9 amino acids in length, derived from a single human immunodeficiency virus gp160 epitope. Antigen processing, thus, gives rise to a rich pool of possible ligands from which MHC class I molecules can choose. The natural peptide set includes a 15-residue-long peptide with unprecedented 6 N-terminal residues that most likely extend out of the MHC class I binding groove. This 15-mer is the longest natural peptide known recognized by cytotoxic T lymphocytes and is surprisingly protected from aminopeptidase trimming in living cells.
Samino
Yolanda
Y
Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Madrid, Spain.
López
Daniel
D
Guil
Sara
S
Saveanu
Loredana
L
van Endert
Peter M
PM
Del Val
Margarita
M
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000276:immunology* / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007739:L Cells; D008024:Ligands; D008074:Lipoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D015534:Trans-Activators / Q000502:physiology
D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D019302:HIV Envelope Protein gp160; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D008074:Lipoproteins; D010446:Peptide Fragments; D015534:Trans-Activators; C500212:tocopherol-associated protein, mouse