Effect of a Single Amino Acid Change in MHC Class I Molecules on the Rate of Progression to AIDS.
Gao, Xiaojiang; Nelson, George W.; Karacki, Peter; Martin, Maureen P.; Phair, John; Kaslow, Richard; Goedert, James J.; Buchbinder, Susan; Hoots, Keith; Vlahov, David; O'Brien, Stephen J.; Carrington, Mary
[Article] New England Journal of Medicine. 344(22):1668-1675, May 31, 2001.

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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-B35,Cw04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B3501, the most common HLA-B35 subtype. We examined subtypes of HLA-B35 in five cohorts and analyzed the relation of structural differences between HLA-B35 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-B35 subtypes with different peptide-binding specificities.

Results: HLA-B35 subtypes were divided into two groups according to peptide-binding specificity: the HLA-B35-PY group, which consists primarily of HLA-B3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B35-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-B35 in accelerating progression to AIDS was completely attributable to HLA-B35-Px alleles, some of which differ from HLA-B35-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-B35-PY and HLA-B35-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. (N Engl J Med 2001;344:1668-75.)

Owned, published, and (C) copyrighted, 2001, by the MASSACHUSETTS MEDICAL SOCIETY