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 3 2 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-de rived factor-1 beta gene transcript (SDF1-3'A). Design 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 Africa n-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 d uring the first 5 years of infection [relative hazard (RH) = 0.22; 95% conf idence interval (CI), 0.012-1.02; P = 0.053]. Similarly, CCR5 wt/Delta 32 c onferred an early protection against severe immune suppression and HIV-1 en cephalopathy, 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 examin ed before 5 years of age (n = 81), the children with CCR5 wt/Delta 32 had s ignificantly lower levels of cell-associated HIV-1 DNA than wild-type homoz ygotes (P = 0.016, adjusted by race), while SDF1-3'A carriers had relativel y higher levels (P = 0.047, adjusted by race). Although the disease-retardi ng effect of CCR5 wt/Delta 32 subsequently disappeared, time to death was s till significantly delayed in the CCR5 Delta 32 heterozygotes without SDF1- 3'A (RH = 0; 95% CI, 0-0.53; P = 0.008). Conclusion 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. (C) 2001 Lippincott Williams & Wilkins.