805-W.
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Polymorphisms in SDF-1 and CCR5 Promoters 59029 and 59353 but not in Promoter 59356 or CCR2 Impact on Disease Progression in HIV-Infected Children
K. K. Singh*1, C. F. Barroga1, M. D. Hughes2, J. Chen2, C. Raskino2, and S. A. Spector1
1Univ. of California, San Diego and 2Harvard Sch. of Publ. Hlth., Boston, MA
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Background: The CCR5delta32/wt genotype can impact on HIV disease of children, but the role of CCR5 promoter, CCR2, and SDF1 genotypes on disease progression are unknown.
Methods: 1057 HIV-infected children (age 42 days to 17 years) from PACTG protocols 152 and 300 who received either (zidovudine) ZDV, didanosine (ddI), ZDV/ddI or ZDV/lamivudine therapy were evaluated for CCR5delta32 and polymorphisms in CCR5 promoters (59029G/A, 59353T/C, and 59356C/T), CCR264I, and SDF1-3'A/G.
Results: At baseline, children with the CCR5delta32/wt genotype vs those with wt/wt had higher CD4+ lymphocyte counts (p=0.005), CD4% (p=0.039), weight for age and gender z-score (p=0.030) and proportion of subjects with cognitive index score >70 (p=0.028), and lower plasma HIV RNA (p=0.033). Only CD4% at baseline varied significantly for genotypes CCR5-59353 (p=0.018), CCR5-59356 (p=0.004) and SDF1 (0.048). In univariate analyses, progression free survival was significantly improved for children with the CCR5delta32/wt (7/64=11%) vs wt/wt genotype (219/985=22%; RH=0.43, p=0.022), promoter polymorphisms 59029-G/G or G/A (153/767=20%) vs A/A (65/249=26%; RH=0.75, p=0.046), and SDF1-3'G/A or G/G (221/1034=21%) vs A/A genotype (7/17=41%; RH=0.47, p=0.046). Children with the CCR5wt/wt genotype and either 59029-G/G or G/A (147/729=20%) had improved progression free survival vs those with the A/A polymorphism (62/220=28%; p=0.010). CCR5-59353C/C (n=381) in univariate analysis did not alter progression free survival but in a multivariate model including CCR5delta32 and CCR5-59029 had a significant independent benefit vs the T/T genotype (p=0.009, RH=0.46). No significant association was found in univariate or multivariate models for the CCR5-59356T/T genotype (n=135) or the CCR264I/I (n=35) or 64I/wt (n=223) polymorphisms.
Conclusions: In addition to the CCR5delta32/wt genotype, CCR5 promoter polymorphisms at positions 59029 and 59353 and SDF-1, but not polymorphisms in CCR5-59356 or CCR2, alter HIV disease progression of children. Baseline plasma HIV RNA predicted the benefit of the delta32/wt genotype but not of CCR5 promoter polymorphisms 59029 or 59353, or SDF-1.
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