Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS.
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.
Gao
X
X
Intramural Research Support Program, Science Applications International Corporation Frederick and the National Cancer Institute, MD, USA.
Nelson
G W
GW
Karacki
P
P
Martin
M P
MP
Phair
J
J
Kaslow
R
R
Goedert
J J
JJ
Buchbinder
S
S
Hoots
K
K
Vlahov
D
D
O'Brien
S J
SJ
Carrington
M
M
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
D015797:HLA-B35 Antigen; D015236:HLA-C Antigens; D010455:Peptides; D018000:Receptors, Peptide