Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.
BACKGROUND
Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results.


OBJECTIVE
To examine postulated associations of genetic alleles with HIV-1 disease progression.


METHODS
Meta-analysis of individual-patient data.


METHODS
19 prospective cohort studies and case-control studies from the United States, Europe, and Australia.


METHODS
Patients with HIV-1 infection who were of European or African descent.


METHODS
Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models.


RESULTS
Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all).


CONCLUSIONS
The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.
Ioannidis
J P
JP
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
Rosenberg
P S
PS
Goedert
J J
JJ
Ashton
L J
LJ
Benfield
T L
TL
Buchbinder
S P
SP
Coutinho
R A
RA
Eugen-Olsen
J
J
Gallart
T
T
Katzenstein
T L
TL
Kostrikis
L G
LG
Kuipers
H
H
Louie
L G
LG
Mallal
S A
SA
Margolick
J B
JB
Martinez
O P
OP
Meyer
L
L
Michael
N L
NL
Operskalski
E
E
Pantaleo
G
G
Rizzardi
G P
GP
Schuitemaker
H
H
Sheppard
H W
HW
Stewart
G J
GJ
Theodorou
I D
ID
Ullum
H
H
Vicenzi
E
E
Vlahov
D
D
Wilkinson
D
D
Workman
C
C
Zagury
J F
JF
O'Brien
T R
TR
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000401:mortality; D000483:Alleles; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics*; D018450:Disease Progression; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D016016:Proportional Hazards Models; D012313:RNA / Q000378:metabolism; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*; D012044:Regression Analysis
C515334:CCR2 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D012313:RNA