HLA class I homozygosity accelerates disease progression in human immunodeficiency virus type I infection

Polymorphic products of HLA class I genes restrict cytotoxic T lymphocyte r esponses to the constantly evolving spectrum of HIV-1 antigens, Accordingly , homozygosity at class I loci can reduce the repertoire for such HLA-depen dent interactions, leading to accelerated disease progression. To test this hypothesis we studied subjects from two distinct HIV/AIDS cohorts: 140 Dut ch homosexual men and 202 Rwandan heterosexual women followed up to 13 year s from HIV-1 seroconversion, We performed intermediate- and selective high- resolution molecular typing at HLA class I (A, B, and C) and high-resolutio n typing at HLA class II DRB1 and DQB1. Homozygosity at the HLA-A or -B loc us or both was found at increasingly high frequency among individuals with successively more rapid progression to late-stage HIV-l-related conditions. In the combined cohorts (n = 342) the odds ratio (OR) due to HLA-A or -B a ntigen homozygosity in rapid versus slow progressors was 3.8 (p = 0.003); f or 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, DR B1, or DQB1 alone, or DRB1-DQB1 haplotypes, did not exert any deleterious e ffect on HIV-1 disease progression, These findings suggest strongly that di versity in addition to sequence specificity at HLA-A and -B loci can influe nce the rate of disease progression following HIV-1 infection.