Protective effect of CCR5 delta 32 heterozygosity is restricted by SDF-1 genotype in children with HIV-1 infection.
OBJECTIVE
To determine the influences on pediatric AIDS of a heterozygous 32 base pair deletion in the CC-chemokine receptor 5 gene (CCR5 wt/Delta 32) and a common polymorphism in the 3' untranslated region of stromal cell-derived factor-1 beta gene transcript (SDF1-3'A).


METHODS
The rate of HIV-1 disease progression and viral burden were compared according to the CCR5 and SDF-1 genotypes in 127 (58 Caucasians, 60 African-Americans and nine Hispanics) perinatally HIV-1-infected children.


RESULTS
Regardless of ethnic background, the CCR5 wt/Delta 32 genotype was associated with a delayed onset of AIDS-defining infectious complications during the first 5 years of infection [relative hazard (RH) = 0.22; 95% confidence interval (CI), 0.012--1.02; P = 0.053]. Similarly, CCR5 wt/Delta 32 conferred an early protection against severe immune suppression and HIV-1 encephalopathy, but only in those without SDF1-3'A (RH = 0; 95% CI, 0--0.70; P = 0.020, and RH = 0; 95% CI, 0--0.71; P = 0.021, respectively). When examined before 5 years of age (n = 81), the children with CCR5 wt/Delta 32 had significantly lower levels of cell-associated HIV-1 DNA than wild-type homozygotes (P = 0.016, adjusted by race), while SDF1-3'A carriers had relatively higher levels (P = 0.047, adjusted by race). Although the disease-retarding effect of CCR5 wt/Delta 32 subsequently disappeared, time to death was still significantly delayed in the CCR5 Delta 32 heterozygotes without SDF1-3'A (RH = 0; 95% CI, 0--0.53; P = 0.008).


CONCLUSIONS
In pediatric AIDS, the protective effect of CCR5 wt/Delta 32 is more pronounced in early years of infection and appears to be abrogated by the SDF1-3'A genotype.
Sei
S
S
HIV Clinical Interface Laboratory, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Boler
A M
AM
Nguyen
G T
GT
Stewart
S K
SK
Yang
Q E
QE
Edgerly
M
M
Wood
L V
LV
Brouwers
P
P
Venzon
D J
DJ
D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000097:blood; D018450:Disease Progression; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015497:HIV-1; D006579:Heterozygote; D006801:Humans; D007223:Infant; D016016:Proportional Hazards Models; D019713:Receptors, CCR5 / Q000235:genetics*; D017384:Sequence Deletion; D016019:Survival Analysis
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004279:DNA, Viral; D019713:Receptors, CCR5