CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS).
BACKGROUND
The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 delta32 and CCR2-641, 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. Promoter-variants were compared in vitro with a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping HIV-1 seroconvertors discordant at polymorphous loci.


RESULTS
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 delta32 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.


CONCLUSIONS
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 delta32 or CCR2-641. 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.
McDermott
D H
DH
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Zimmerman
P A
PA
Guignard
F
F
Kleeberger
C A
CA
Leitman
S F
SF
Murphy
P M
PM
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D000483:Alleles; D001483:Base Sequence; D015331:Cohort Studies; D004247:DNA; D018450:Disease Progression; D015497:HIV-1; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics
D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D004247:DNA