Adverse effect of the CCR5 promoter -2459A allele on HIV-1 disease progression.
HIV positive individuals heterozygous for a 32 basepair deletion in the CCR5 encoding gene (CCR5 Delta32) have a reduced number of CCR5 receptors on the cell surface and a slower progression towards AIDS and death. Other human polymorphisms, such as the CCR2 64I and the CCR5 promoter -2459 A/G transition that has been discovered recently, have also been shown to influence HIV progression. Since genetic linkages make these polymorphisms interdependent variables, the aim of the present study was to isolate and evaluate the effect on HIV disease progression for each of these mutations independently. Genotypes were determined in 119 individuals enrolled in the Copenhagen AIDS Cohort. When including the concurrent effects of the CCR5 Delta32 and CCR2 64I mutations, homozygous carriers of the CCR5 promoter -2459A allele had a significantly faster progression towards death than heterozygous A/G individuals (P = 0.03), whereas this adverse effect was not significant when comparing A/A and G/G individuals. However, independent analysis revealed a significant adverse effect of the CCR5 promoter -2459A allele. Homozygous carriers of the -2459A allele that lack the protective effects of the CCR5 Delta32 and CCR2 64I mutations were found to have a median survival of 6.0 years, whereas carriers of the -2459G allele had a median survival of 9.4 years (P < 0.01).
Knudsen
T B
TB
Clinical Research Unit, Copenhagen University Hospitals Hvidovre, Kettegaard allé 50, 2650 Hvidovre, Denmark.
Kristiansen
T B
TB
Katzenstein
T L
TL
Eugen-Olsen
J
J
D000483:Alleles; D015331:Cohort Studies; D018450:Disease Progression; D005838:Genotype; D015658:HIV Infections / Q000401:mortality / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006720:Homozygote; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine