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Previous Volume 344:1668-1675 May 31, 2001 Number 22 Next

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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.

Source Information

From the Intramural Research Support Program, Science Applications International Corporation Frederick and the National Cancer Institute, Frederick, Md. (X.G., G.W.N., M.P.M., M.C.); Johns Hopkins School of Medicine, Baltimore (P.K.); Northwestern University Medical School Comprehensive AIDS Center, Chicago (J.P.); the Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham (R.K.); the Viral Epidemiology Branch, National Cancer Institute, Bethesda, Md. (J.J.G.); the San Francisco Department of Public Health, San Francisco (S.B.); the Gulf States Hemophilia Center, University of Texas Health Science Center, Houston (K.H.); Johns Hopkins School of Hygiene and Public Health, Baltimore (D.V.); and the Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Md. (S.J.O.). This article is dedicated to the memory of Dr. Janis Giorgi, a longtime friend and colleague.

Address reprint requests to Dr. Carrington at P.O. Box B, NCI-FCRDC, Frederick, MD 21702, or at carringt{at}mail.ncifcrf.gov.

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