EPIDEMIOLOGY AND SOCIAL SCIENCE Dominant Effects of CCR2–CCR5 Haplotypes in HIV-1 Disease Progression

Summary: Three haplotypes for the CCR2–CCR5 region previ-ously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contribu-tions to AIDS progression of CCR2 64I, CCR5 32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included pa-tients representing the extremes of the distribution for AIDS progres-sion: rapid progressors (RP) who developed CD4+ T-cell counts of <300 / mm3 within 3 years after the last HIV-1–seronegative test and slow progressors (SP) who were HIV-1 infected for 8 years with CD4+ T-cell counts of>500/mm3. Comparing the RP with a serocon-verter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the inter-mediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progession; the tendency towards a disproportion-ately early effect was significant for CCR5 32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype dis-tribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression