The strongest susceptibility to progression from HIV-1 infection to AIDS is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. In the May 31 New England Journal of Medicine, Xiaojiang Gao and colleagues from Johns Hopkins School of Medicine, Baltimore shows that a single amino-acid change in HLA molecules has a substantial effect on the rate of progression to AIDS.

Gao et al. genotyped HLA class I loci for 850 patients who seroconverted and had known dates of HIV-1 infection. 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 (excluding tyrosine) in position 9. Survival analyses showed a rapid progression to AIDS in patients with HLA-B*35-Px alleles and a slower progression in patients with HLA-B*35-PY alleles, some of which differ from HLA-B*35-Px by only one amino acid residue (NEJM 2001, 344:1668-1675).

The effect is probably attributable to an inappropriate cytotoxic-T-lymphocyte response in patients with HLA-B*35-Px, whereas a comparatively protective response occurs in patients with HLA-B*35-PY that corresponds with the slower progression to disease in these patients.