THE MHC CLASS-I RESTRICTED IMMUNE-RESPONSE TO HIV-GAG IN BALB C MICE SELECTS A SINGLE EPITOPE THAT DOES NOT HAVE A PREDICTABLE MHC-BINDING MOTIF AND BINDS TO K-D THROUGH INTERACTIONS BETWEEN A GLUTAMINE AT P3 AND POCKET-D/

Citation
M. Mata et al., THE MHC CLASS-I RESTRICTED IMMUNE-RESPONSE TO HIV-GAG IN BALB C MICE SELECTS A SINGLE EPITOPE THAT DOES NOT HAVE A PREDICTABLE MHC-BINDING MOTIF AND BINDS TO K-D THROUGH INTERACTIONS BETWEEN A GLUTAMINE AT P3 AND POCKET-D/, The Journal of immunology (1950), 161(6), 1998, pp. 2985-2993
Citations number
58
Categorie Soggetti
Immunology
ISSN journal
00221767
Volume
161
Issue
6
Year of publication
1998
Pages
2985 - 2993
Database
ISI
SICI code
0022-1767(1998)161:6<2985:TMCRIT>2.0.ZU;2-Y
Abstract
Using a strain of Listeria monocytogenes that stably expresses and sec retes HIV gag to deliver this Ag to the MHC class I pathway of Ag proc essing, we have identified the immunodominant CTL epitope to gag in th e BALB/c mouse and shown that it is K-d restricted. The specific motif for the peptides that bind the MHC class I molecule H-2 K-d is believ ed to be a nonamer with residues tyrosine or phenylalanine in the seco nd amino acid position and leucine or isoleucine in the carboxyl-termi nal or ninth amino acid position as dominant anchoring positions. Surp risingly, the identified gag peptide, AMQMLKETI, does not contain an a nchoring aromatic residue in position two although competition assays with other K-d-restricted epitopes indicated that it binds to K-d with comparable affinity. Using a theoretical molecular dynamics approach to probe the stability of peptide binding to MHC class I molecules, we show that the absence of an appropriate anchor residue at P2 in AMQML KETI is compensated by favorable interactions of the glutamine at P3 w ith pocket D of K-d. These findings were verified experimentally, demo nstrating the predictive power of this theoretical approach in analyzi ng MHC class I/peptide interactions. These studies also indicate that CTL epitope prediction that relies on dominant peptide moths may not a lways identify the correct epitope.