Eotaxin is a potent chemoattractant for eosinophils, basophils, certain T-cell subsets and various neurological cells. As far as AIDS is concerned, CCR3 the eotaxin receptor, may be used as a co-receptor for cell entry by certain dual-tropic strains of HIV-1. Three novel single nucleotide polymorphisms (SNPs) were identified in the eotaxin gene. Two are in the promoter region, 1328 bp and 329 bp upstream of the RNA start site, while the third occurs 122 bp downstream of the start site in exon 1 and causes an alanine to threonine substitution in the last amino acid of the signal peptide. Association analyses of well documented AIDS cohorts reveals significant associations wih five different clinical phenotypes; two with infection and three with progression. Genotypes containing the G-1328A variant occur at a higher frequency in Caucasian exposed uninfected and high-risk exposed uninfected patients compared to seroconvertors. This protective effect was significant in combined cohort, MACS, and homosexual comparisons. Alternatively, genotypes having the G122A substitution are present at higher frequencies in Caucasian seroconvertors than in either uninfected group. This susceptible effect is significant in the combined cohort, MHCS and hemophiliac groups. These effects on infection are shown to be independent using logistic regression. Three associations with disease progression were noted. First, the G122A change is associated with more rapid advancement to death in the MACS. Second, the A-329G change is associated with more rapid progression to four AIDS-defining endpoints in African Americans. Third, a haplotype (haplotype B) containing 58% of the Caucasian A-329G alleles on an otherwise wild type background is associated with retarded progression to the AIDS93 endpoint in the MACS. The exact mechanisms whereby these polymorphisms affect HIV-1 infection and progression are unclear, however, the two promoter mutations may influence transcription of the gene and the change in exon 1 may inhibit cleavage of the signal peptide.
| Modi, William S; O'Brien, Thomas R; Vlahov, David et al. (2003) Haplotype diversity in the interleukin-4 gene is not associated with HIV-1 transmission and AIDS progression. Immunogenetics 55:157-64 |
| Modi, William S; Goedert, James J; Strathdee, Steffanie et al. (2003) MCP-1-MCP-3-Eotaxin gene cluster influences HIV-1 transmission. AIDS 17:2357-65 |
