Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study

Objective: To examine whether polymorphism in the RANTES gene is associated with HIV disease outcome. Design: RANTES, a ligand of the major HIV co-receptor, CCR5, is known to bl ock HIV-CCR5 interactions. Recently, two single nucleotide polymorphisms in the RANTES gene promoter region, designated -403G/A and -28C/G, have been described. Both polymorphisms can affect in-vitro promoter activity, and th e RANTES -403A, -28G haplotype has been associated with a slower CD4 cell c ount decline rate in a Japanese cohort. Methods: We compared RANTES compound genotype frequencies between HIV-posit ive and exposed-uninfected participants of the Multicenter AIDS Cohort Stud y (MACS) and rates of progression to AIDS for MACS seroconverters. Results: We found that the two most common RANTES promoter compound genotyp es, G1 (-403G/G, -28C/C) found in 67% of Caucasians, and G4 (-403G/A, -28C/ C) found in 23% of Caucasians, were associated with altered risk of HIV tra nsmission and progression, particularly in individuals who lacked the prote ctive CCR5 mutation, CCR5 Delta 32. In this study, individuals with a G4 co mpound genotype were more likely to acquire HIV than individuals with a G1 compound genotype (OR 1.72, P = 0.016) and the risk increased when individu als possessing CCR5 Delta 32 were omitted from consideration (OR 2.13, P = 0.005). Among seroconverters lacking CCR5 Delta 32, those who had the G4 co mpound genotype progressed significantly slower to AIDS-1993 than those wit h the G1 compound genotype (median time to AIDS 7.6 versus 5.4 years; RH 0. 65; P = 0.007). Conclusions: These data implicate the RANTES-403A allele as a risk factor f or HIV transmission and as a protective factor for HIV progression. (C) 200 0 Lippincott Williams & Wilkins.