HLA Class I Homozygosity Accelerates Disease Progression in Human Immunodeficiency Virus Type 1 Infection

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Abstract
Polymorphic products of HLA class I genes restrict cytotoxic T lymphocyte responses to the constantly evolving spectrum of HIV-1 antigens. Accordingly, homozygosity at class I loci can reduce the repertoire for such HLA-dependent interactions, leading to accelerated disease progression. To test this hypothesis we studied subjects from two distinct HIV/AIDS cohorts: 140 Dutch homosexual men and 202 Rwandan heterosexual women followed up to 13 years from HIV-1 seroconversion. We performed intermediate- and selective highresolution molecular typing at HLA class I (A , B , and C) and high-resolution typing at HLA class II DRB1 and DQB1 . Homozygosity at the HLA-A or -B locus or both was found at increasingly high frequency among individuals with successively more rapid progression to late-stage HIV-1-related conditions. In the combined cohorts (n = 342) the odds ratio (OR) due to HLA-A or-B antigen homozygosity in rapid versus slow progressors was 3.8 (p = 0.003); for Dutch men alone the OR was 3.5 (p = 0.102), and for Rwandan women the OR was 4.1 (p = 0.009). In contrast, homozygous genotypes at either HLA-C, DRB1, or DQB1 alone, or DRB1- DQB1 haplotypes, did not exert any deleterious effect on HIV-1 disease progression. These findings suggest strongly that diversity in addition to sequence specificity at HLA-A and -B loci can influence the rate of disease progression following HIV-1 infection.