Influence of CUL5 genetic variants on HIV-1 vertical transmission and progression to AIDS in Argentinean infected children

DE MAIO, FEDERICO ANDRÉS; ROCCO, CARLOS; AULICINO, PAULA; BOLOGNA, ROSA; SEN, LUISA; MANGANO, ANDREA

Ciudad de México

Conferencia; XVII International AIDS Conference; 2008

International AIDS Society (IAS)

Background: HIV-1 Vif protein acts as the substrate receptor in a Cullin 5-containing E3 ubiquitin ligase complex that is responsible for the degradation of the antiretroviral factors APOBEC3. The CUL5 gene, encoding Cullin 5 protein, presents an intronic single nucleotide polymorphism (SNP) A/G referred as rs11212495 in NCBI dbSNP. The minor allele G has been associated with a more rapid CD4+ T cell loss in African-American but not in European-American HIV-infected patients. The aim of this study was to evaluate the effect of the CUL5 A/G SNP on HIV-1 vertical transmission and disease progression in a Hispanic-Caucasian cohort of perinatally HIV-exposed children. Methods: The studied population included 109 HIV-exposed uninfected children (47% female and 53% male) and 102 infected patients (56% female and 44% male). The median follow-up of the infected children was 33 months and 67.6% developed AIDS. CUL5 genotyping was assessed by PCR-RFLP assays. Hardy-Weinberg equilibrium and frequency differences were tested with Pearson chi square. Time curves for AIDS progression were estimated with Kaplan-Meier methods. Hazard ratio was estimated with Cox proportional hazards models. Results: CUL5 genotypes showed no deviation from Hardy-Weinberg equilibrium in uninfected (AA=85.32%, AG=12.84%, GG=1.83%) and HIV-infected (AA=88.24%, AG=10.78%, GG=0.98%) children and no statistically significant differences for G allele frequencies (0.083 and 0.064, respectively) were observed. Kaplan-Meier analysis of time to AIDS showed that AG heterozygotes children (n=11) had a slower progression to AIDS than AA homozygotes (n=90) (RH=0.652, p=0.038 likelihood ratio test). The median progression time of AA individuals was 36.2 months, while only 18.2% AG patients progressed to AIDS in the same period. An unchanged trend was observed for models adjusted for sex, CCR5D32 and SDF1-3´ A genotypes. Conclusions: Our results suggest that the CUL5 G allele does not modify HIV-1 mother-to-child transmission but exert a protective effect on progression to pediatric AIDS.