GROUPING HLA-B LOCUS SEROLOGIC SPECIFICITIES ACCORDING TO SHARED STRUCTURAL MOTIFS SUGGESTS THAT DIFFERENT PEPTIDE-ANCHORING POCKETS MAY HAVE CONTRASTING INFLUENCES ON THE COURSE OF HIV-1 INFECTION
S. Itescu et al., GROUPING HLA-B LOCUS SEROLOGIC SPECIFICITIES ACCORDING TO SHARED STRUCTURAL MOTIFS SUGGESTS THAT DIFFERENT PEPTIDE-ANCHORING POCKETS MAY HAVE CONTRASTING INFLUENCES ON THE COURSE OF HIV-1 INFECTION, Human immunology, 42(1), 1995, pp. 81-89
Two different groups of HLA-B specificities were associated with two c
ontrasting outcomes of HIV-1 infection. HLA-B45, -B49, and -B50 were e
ach found at a moderately increased frequency among individuals respon
ding to HIV-1 infection with a marked circulating and infiltrative CD8
T-cell lymphocytosis, a slow rate of CD4 T-cell decline, very low fre
quency of opportunistic infections, and low viral strain heterogeneity
. In contrast, among HIV-infected individuals with more rapid progress
ion to opportunistic infections, HLA-B35 was found to be increased in
frequency and to act as a dominant marker for this adverse outcome. HL
A-B45, -B49, and -B50 contain identical peptide-anchoring ''B'' and ''
C-terminal'' pocket structures, which differ greatly from those presen
t in HLA-B35, implying that different immunogenic peptides are likely
to be bound by these two groups of alleles. Placing HLA-B45, -B49, and
-B50 into one structurally defined group revealed a much stronger and
statistically significant association with the CD8 lymphocytosis synd
rome (OR = 5.3, p = 0.0005). The B pocket structure in these alleles c
ontains an easily accessible lysine residue at position 45, suggesting
that the P2 or P3 anchor residue of a bound peptide is negatively cha
rged. Additionally, by observing the effect on the ORs of adding struc
tures containing amino acid substitutions in the C-terminal pocket- of
HLA-B45, -B49, and -B50, this region was also shown to influence susc
eptibility to this host response. These results suggest that, when ana
lyzing HLA disease susceptibility and resistance associations, groupin
g HLA specificities according to regions of shared structure and resis
tance associations, grouping HLA specificities according to regions of
shared structure and peptide-binding function may provide insight int
o disease mechanisms involving binding of immunogenic peptides. Moreov
er, they suggest the possibility that various peptide-anchoring struct
ures present in MHC class I molecules may contribute ro different outc
omes of HIV-1 infection, possibly by initiating qualitatively differen
t host immune responses.