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

Citation
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
Citations number
32
Categorie Soggetti
Immunology
Journal title
ISSN journal
01988859
Volume
42
Issue
1
Year of publication
1995
Pages
81 - 89
Database
ISI
SICI code
0198-8859(1995)42:1<81:GHLSSA>2.0.ZU;2-L
Abstract
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.