Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis.
OBJECTIVE
Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis.


METHODS
Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated.


RESULTS
There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed.


CONCLUSIONS
The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.
Ioannidis
John P A
JP
Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. jioannid@cc.uoi.gr
Contopoulos-Ioannidis
Despina G
DG
Rosenberg
Philip S
PS
Goedert
James J
JJ
De Rossi
Anita
A
Espanol
Teresa
T
Frenkel
Lisa
L
Mayaux
Marie-Jeanne
MJ
Newell
Marie-Louise
ML
Pahwa
Savita G
SG
Rousseau
Christine
C
Scarlatti
Gabriella
G
Sei
Shizuko
S
Sen
Luisa
L
O'Brien
Thomas R
TR
D000483:Alleles; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D018450:Disease Progression; D005500:Follow-Up Studies; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000401:mortality; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011446:Prospective Studies; 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