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.


METHODS
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
These data implicate the RANTES-403A allele as a risk factor for HIV transmission and as a protective factor for HIV progression.
McDermott
D H
DH
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Beecroft
M J
MJ
Kleeberger
C A
CA
Al-Sharif
F M
FM
Ollier
W E
WE
Zimmerman
P A
PA
Boatin
B A
BA
Leitman
S F
SF
Detels
R
R
Hajeer
A H
AH
Murphy
P M
PM
D000163:Acquired Immunodeficiency Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000635:transmission; D000349:Africa / Q000453:epidemiology; D000483:Alleles; D018946:Chemokine CCL5 / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015658:HIV Infections / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000635:transmission*; D006679:HIV Seropositivity / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000635:transmission; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009656:North America / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics; D015996:Survival Rate
D018946:Chemokine CCL5