Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS
A particular HLA class I molecule elicits antigenic responses with T lymphocytes and initiates a specific immune response and the clearance of foreign material.
The genes (alleles) that encode HLA class I molecules are highly changeable or “polymorphic” amino acids. The great diversity of the amino acids may be due to selections over time enabling mammals to resist a wide variety of pathogens. If this model explains the diversity of class I molecules, the amino acids encoding functionally distinct molecules should provide a range of protection against a given pathogen, and give definitive clues for an HIV vaccine.
Matching HLA alleles to the defence against a particular infectious disease has been difficult for several reasons. Because of the extreme variability and even distribution of alleles that characterize the HLA loci, studies would require large cohorts to achieve sufficient statistical power. The effects of the genetic makeup of the host on infectious diseases are complex and may involve multiple loci, a fact that complicates analyses of the influence of HLA alleles on disease. The patterns of linkage among the many functionally related loci in the major-histocompatibility-complex (MHC) genes also make it difficult to identify the causative disease locus.
HLA-B*35, which almost always neighbours HLA-Cw*04 on chromosome 6, has been the only allele consistently associated with rapid progression to AIDS among a large number of conflicting or unconfirmed associations between HLA alleles and various outcomes in patients with human immunodeficiency virus type 1 (HIV-1). Strong evidence for an effect of HLA-B*35,Cw*04 on progression to AIDS has been observed in white but not in black HIV-infected patients for whom the date of seroconversion is known.
The difference between white and black progression rates to AIDS has raised the further question of whether the causative HLA-B*35 or HLA-Cw*04 operates immunologically or, alternatively, is simply associated with another locus that accelerates the progression to AIDS. However, according to the authors, because the molecule encoded by HLA-B*3501 is known to bind and present a variety of HIV-1 antigenic epitopes and to induce cytotoxic-T-lymphocyte responses, the susceptibility associated with HLA-B*35 cannot be attributed to an inability of HLA-B*3501 to elicit cytotoxic-T-lymphocyte reactivity.
Finally, previous studies have shown that the differences in the amino acid sequences of the HLA class I peptide-binding region affect the binding of peptides. In this study, the authors investigated the rate of progression to AIDS among patients with subtypes of HLA-B*35 alleles that correlate with the peptide-binding properties of each subtype.
The authors “examined subtypes of HLA-B*35 in five cohorts and analysed the relation of structural differences between HLA- B*35 subtypes to the risk of progression to AIDS. Using genotyping of HLA class I loci 850 patients who seroconverted and had known dates of HIV-1 infection, the investigators analysed the rate of progression to AIDS “to identify the effects of closely related HLA-B*35 subtypes with different peptide-binding specificities.”
The results indicated, according to the authors, “The influence of HLA-B*35 in accelerating progression to AIDS.” This 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.
The results of the study were significant and showed 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.” In addition, “The use of large, clinically well-defined cohorts in this study has allowed the identification of specific subtypes of HLA-B*35 as responsible for the previously reported association between HLA-B*35 and rapid progression to AIDS. The most common HLA-B*35 subtype allele, HLA-B*3501, has little or no effect on progression to AIDS in either white or black patients. The finding that specific HLA-B*35-Px subtypes have similar effects in blacks and whites strongly supports the hypothesis that these HLA-B alleles exert an effect on the immune response to HIV-1 disease.”
Gao X, Nelson GW, Karacki P et al. New England Journal of Medicine (05.31.01) Vol 344; No 22: P 1668-1675.
Source: CDC HIV/STD/TB Prevention News Update