Molecular analysis of presentation by HLA-A2.1 of a promiscuously binding V3 loop peptide from the HIV-envelope protein to human cytotoxic T lymphocytes.
P18(IIIB) is a highly immunogenic peptide from the V3 loop of the HIV-1 gp160 envelope protein that is presented promiscuously by multiple class I MHC molecules. Understanding the molecular basis for promiscuous presentation may have many practical applications. As the highly prevalent HLA-A2.1 class I molecule is known to present P18(IIIB) for recognition by cytotoxic T lymphocytes (CTL) found in peripheral blood mononuclear cells of HIV+ donors, a P18(IIIB)-specific CTL line was generated from and HLA-A2(+), HIV- donor in order to define the molecular basis for, and ultimately improve upon the binding of, this peptide to HLA-A2.1. The minimal epitope recognized by the line was a decamer, I10, with the sequence RGPGRAFVTI. Interestingly, this decamer is identical to the minimal epitope from P18(IIIB) seen by murine CTL restricted by H-2Dd. A panel of Ala-substituted peptides was employed in MHC-binding and T cell response studies to identify MHC- and TCR-binding residues. Notably, many of the agretopic and epitopic residues identified were identical to those involved in the corresponding interactions of I10 with the H-2Dd MHC molecule and murine I10-specific CTL. The I10 peptide does not contain the described HLA-A2.1 binding motif. Instead a Pro at P3, a Phe at P7 and an Ile at P10 are utilized for MHC binding. Agretopic residue similarities with the hepatitis B nucleocapsid decamer suggest that these residues may comprise an alternative motif of anchors utilized by decamers for binding to HLA-A2.1.
Alexander-Miller
M A
MA
Metabolism Branch, NCI NIH, Bethesda, MD 20892-1578, USA.
Parker
K C
KC
Tsukui
T
T
Pendleton
C D
CD
Coligan
J E
JE
Berzofsky
J A
JA
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D015686:Gene Products, env / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015686:Gene Products, env; D015488:HIV Antigens; D019302:HIV Envelope Protein gp160; C087213:HIV-1 gp160 (315-329); D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell