title: Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS.
abstract: BACKGROUND
  From studies of genetic polymorphisms and the rate of progression from human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS), it appears that the strongest susceptibility is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B*3501, the most common HLA-B*35 subtype. We examined subtypes of HLA-B*35 in five cohorts and analyzed the relation of structural differences between HLA-B*35 subtypes to the risk of progression to AIDS.
  
  
  METHODS
  Genotyping of HLA class I loci was performed for 850 patients who seroconverted and had known dates of HIV-1 infection. Survival analyses with respect to the rate of progression to AIDS were performed to identify the effects of closely related HLA-B*35 subtypes with different peptide-binding specificities.
  
  
  RESULTS
  HLA-B*35 subtypes were divided into two groups according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but can bind several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-PY alleles by only one amino acid residue.
  
  
  CONCLUSIONS
  This analysis shows that, in patients with HIV-1 infection, a single amino acid change in HLA molecules has a substantial effect on the rate of progression to AIDS. The different consequences of HLA-B*35-PY and HLA-B*35-Px in terms of disease progression highlight the importance of the epitope specificities of closely related class I molecules in the immune defense against HIV-1.
authors.affiliation: Intramural Research Support Program, Science Applications International Corporation Frederick and the National Cancer Institute, MD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: G W
authors.initials: GW
authors.lastname: Nelson
authors.forename: P
authors.initials: P
authors.lastname: Karacki
authors.forename: M P
authors.initials: MP
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Phair
authors.forename: R
authors.initials: R
authors.lastname: Kaslow
authors.forename: J J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: S
authors.initials: S
authors.lastname: Buchbinder
authors.forename: K
authors.initials: K
authors.lastname: Hoots
authors.forename: D
authors.initials: D
authors.lastname: Vlahov
authors.forename: S J
authors.initials: SJ
authors.lastname: O'Brien
authors.forename: M
authors.initials: M
authors.lastname: Carrington
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D044383:Black People / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D005805:Genes, MHC Class I; D005838:Genotype; D015658:HIV Infections / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D015797:HLA-B35 Antigen / Q000737:chemistry / Q000235:genetics*; D015236:HLA-C Antigens; D006801:Humans; D010455:Peptides / Q000378:metabolism; D016016:Proportional Hazards Models; D018000:Receptors, Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D015797:HLA-B35 Antigen; D015236:HLA-C Antigens; D010455:Peptides; D018000:Receptors, Peptide