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.
Two different groups of HLA-B specificities were associated with two contrasting outcomes of HIV-1 infection. HLA-B45, -B49, and -B50 were each found at a moderately increased frequency among individuals responding to HIV-1 infection with a marked circulating and infiltrative CD8 T-cell lymphocytosis, a slow rate of CD4 T-cell decline, very low frequency of opportunistic infections, and low viral strain heterogeneity. In contrast, among HIV-infected individuals with more rapid progression to opportunistic infections, HLA-B35 was found to be increased in frequency and to act as a dominant marker for this adverse outcome. HLA-B45, -B49, and -B50 contain identical peptide-anchoring "B" and "C-terminal" pocket structures, which differ greatly from those present 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 syndrome (OR = 5.3, p = 0.0005). The B pocket structure in these alleles contains an easily accessible lysine residue at position 45, suggesting that the P2 or P3 anchor residue of a bound peptide is negatively charged. Additionally, by observing the effect on the ORs of adding structures containing amino acid substitutions in the C-terminal pocket of HLA-B45, -B49, and -B50, this region was also shown to influence susceptibility to this host response.(ABSTRACT TRUNCATED AT 250 WORDS)
Itescu
S
S
Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Rose
S
S
Dwyer
E
E
Winchester
R
R
D017088:AIDS-Related Opportunistic Infections / Q000235:genetics / Q000276:immunology; D000328:Adult; D017951:Antigen Presentation; D001665:Binding Sites; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes; D002648:Child; D018450:Disease Progression; D004198:Disease Susceptibility / Q000276:immunology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D015235:HLA-B Antigens / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000276:immunology; D015797:HLA-B35 Antigen / Q000737:chemistry; D006801:Humans; D018655:Lymphocyte Count; D008239:Lysine / Q000737:chemistry; D010446:Peptide Fragments / Q000276:immunology*; D011485:Protein Binding; D011487:Protein Conformation
D015235:HLA-B Antigens; D015797:HLA-B35 Antigen; C077377:HLA-B45 antigen; D010446:Peptide Fragments; D008239:Lysine