CCR5 promoter polymorphism and HIV-1 disease progression

Background The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 Δ32 and CCR2-64I, which alter the protein-coding regions for the HIV-1 coreceptors/chemokine receptors CCR5 and CCR2b. We tested the hypothesis that polymorphisms of the CCR5 promoter might affect the rate of progression of HIV-1 infected people to AIDS. Methods We used directed heteroduplex analysis to identify polymorphism in the CCR5 promoter. Promotervariants were compared in vitro with a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping HIV-1 seroconvertors discordant at polymorphous loci. Findings An A/G polymorphism was identified at basepair 59029 (Genbank U95626) in the CCR5 promoter. Both promoter alleles were common (43–68% allelic frequency for 59029-A depending on race). When in-vitro promoter activity was measured, 59029-G had 45% lower activity than 59029-A (p=0·05). In a cohort of HIV-1 seroconvertors lacking both CCR5 Δ32 and CCR2-641, 59029-G/G individuals progressed to AIDS on average 3·8 years more slowly than 59029-A/A individuals (p=0·004). 59029-G/A discordance did not correlate with discordant rates of infection. Interpretation Our results are consistent with the hypothesis that CCR5 is important in HIV-1 pathogenesis. CCR5 59029-G/G appears to be protective relative to CCR5 59029-A/A, and about twice as protective relative to CCR5 Δ32 or CCR2-64I. This effect may be the result of reduced CCR5 mRNA production. These results identify the first site in the CCR5 promoter that may be a useful target for treatment of HIV-1 infection.