Effects of CCR5-Delta32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection.
OBJECTIVE
To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression.


METHODS
Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia.


METHODS
We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion.


RESULTS
Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter.


CONCLUSIONS
The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.
Mulherin
Stephanie A
SA
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH/DHHS, 6120 Executive Boulevard, Rockville, MD 20852, USA.
O'Brien
Thomas R
TR
Ioannidis
John P
JP
Goedert
James J
JJ
Buchbinder
Susan P
SP
Coutinho
Roel A
RA
Jamieson
Beth D
BD
Meyer
Laurence
L
Michael
Nelson L
NL
Pantaleo
Giuseppe
G
Rizzardi
G Paolo
GP
Schuitemaker
Hanneke
H
Sheppard
Haynes W
HW
Theodorou
Ioannis D
ID
Vlahov
David
D
Rosenberg
Philip S
PS
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D018450:Disease Progression; D006679:HIV Seropositivity / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*; D016019:Survival Analysis; D013997:Time Factors
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine