From Genome to Life:

VASILESCU Alexandre

Centre National de Genotypage, Gene Identification And Snp Discovery, 2, Rue Gaston Cremieux, Evry 91000, France

title: Genomic analysis of th1/th2 cytokine genes : pivotal role of il10, il12 and ifng in hiv-1 infection and disease progression

We performed a comprehensive analysis on the role of the Th1/Th2 cytokine genes (IL12 p35 and p40, IL2, IFNg, IL4, IL6, IL10, IL13) in AIDS, by comparing their genetic distributions in the GRIV cohort. 500 Caucasian individuals, including highly selected nonprogressor and very rapid progressor seropositive patients and seronegative controls, were exhaustively genotyped using a PCR/sequencing approach. Fifty-one frequent polymorphisms (SNPs) were found of which, 35 were not previously known or well-characterized. Highly significant SNP associations were found which were further confirmed with haplotypes. IL10 appeared as the main cytokine both for its effect on infection and on disease progression with for instance a RR equal to 9 for the SNP IL10 4 (p=0,0005). Weaker associations between haplotypes and disease were also observed for IFNg, IL2, IL4, and IL12p35 and p40 (RR between 0.5 and 2). No association was observed for IL6 or IL13. None of the significant associations was connected to a protein mutation, thus outlining the importance of the regulation of cytokine expression. Interactions between haplotypes were also investigated. Most striking associations were found for the haplotypic combinations of IL12p40 with IFNg (RR=13.8, p=0.0008) for fast progression, and of IL12p35 with IL10 (RR=5.5, p=0.0005) for prevention of infection. Our results suggest that cytokines are involved in the natural resistance to HIV-1 and that the immune system is able to clear the virus, at least in the early stages. This result strongly supports the development of immune-based interventions in AIDS.