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

• Published in: AIDS (London) Vol. 14; no. 17; pp. 2671 - 2678
• Main Authors: MCDERMOTT, David H, BEECROFT, Matthew J, MURPHY, Philip M, KLEEBERGER, Cynthia A, AL-SHARIF, Fadwa M, OLLIER, William E. R, ZIMMERMAN, Peter A, BOATIN, Boakye A, LEITMAN, Susan F, DETELS, Roger, HAJEER, Ali H
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-12-2000
• Subjects: Acquired Immunodeficiency Syndrome - diagnosis; Acquired Immunodeficiency Syndrome - epidemiology; Acquired Immunodeficiency Syndrome - genetics; Acquired Immunodeficiency Syndrome - transmission; Africa - epidemiology; AIDS/HIV; Alleles; Biological and medical sciences; Chemokine CCL5 - genetics; Cohort Studies; Continental Population Groups - genetics; Disease Progression; Ethnic Groups - genetics; Gene Frequency - genetics; Genetic Predisposition to Disease - genetics; Haplotypes - genetics; HIV Infections - diagnosis; HIV Infections - epidemiology; HIV Infections - genetics; HIV Infections - transmission; HIV Seropositivity - diagnosis; HIV Seropositivity - epidemiology; HIV Seropositivity - genetics; HIV Seropositivity - transmission; Human viral diseases; Humans; Infectious diseases; Medical sciences; North America - epidemiology; Polymorphism, Genetic - genetics; Prognosis; Promoter Regions, Genetic - genetics; Survival Rate; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; North America; Africa; Immunopathology; Prognosis; Genetic variability; RANTES; Multicenter study; AIDS; Immune deficiency; Infection; Chemokine; Promoter; Gene; Viral disease; Cohort study; Risk factor; Evolution; Polymorphism
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/00002030-200012010-00006

To examine whether polymorphism in the RANTES gene is associated with HIV disease outcome.
RANTES, a ligand of the major HIV co-receptor, CCR5, is known to block 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 the RANTES -403A, -28G haplotype has been associated with a slower CD4 cell count decline rate in a Japanese cohort.
We compared RANTES compound genotype frequencies between HIV-positive and exposed-uninfected participants of the Multicenter AIDS Cohort Study (MACS) and rates of progression to AIDS for MACS seroconverters.
We found that the two most common RANTES promoter compound genotypes, 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 transmission and progression, particularly in individuals who lacked the protective CCR5 mutation, CCR5delta32. In this study, individuals with a G4 compound 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 individuals possessing CCR5delta32 were omitted from consideration (OR 2.13, P = 0.005). Among seroconverters lacking CCR5delta32, those who had the G4 compound genotype progressed significantly slower to AIDS-1993 than those with the G1 compound genotype (median time to AIDS 7.6 versus 5.4 years; RH 0.65; P = 0.007).
These data implicate the RANTES-403A allele as a risk factor for HIV transmission and as a protective factor for HIV progression.