Dominant effects of CCR2-CCR5 haplotypes in HIV-1 disease progression.
Three haplotypes for the CCR2-CCR5 region previously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contributions to AIDS progression of CCR2 64I, CCR5 Delta32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included patients representing the extremes of the distribution for AIDS progression: rapid progressors (RP) who developed CD4 T-cell counts of <300/ mm within 3 years after the last HIV-1-seronegative test and slow progressors (SP) who were HIV-1 infected for > or =8 years with CD4 T-cell counts of >500/mm. Comparing the RP with a seroconverter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 Delta32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the intermediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progression; the tendency towards a disproportionately early effect was significant for CCR5 Delta32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype distribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression.
Winkler
Cheryl A
CA
Laboratory of Genomic Diversity, Division of Basic Research, SAIC-Frederick, NCI, Frederick, MD, USA.
Hendel
Houria
H
Carrington
Mary
M
Smith
Michael W
MW
Nelson
George W
GW
O'brien
Stephen J
SJ
Phair
John
J
Vlahov
David
D
Jacobson
Lisa P
LP
Rappaport
Jay
J
Vasilescu
Alexandre
A
Bertin-Maghit
Sebastien
S
An
Ping
P
Lu
Wei
W
Andrieu
Jean-Marie
JM
Schächter
François
F
Therwath
Amu
A
Zagury
Jean-François
JF
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005500:Follow-Up Studies; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1; D006239:Haplotypes / Q000502:physiology*; D006801:Humans; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*; D044465:White People
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine