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/
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
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.