Background:  Interleukin (IL) -7 is a critical factor for homeostasis of the memory T cell pool and thymopoiesis. A dysregulation of IL-7RA function has been described in HIV infection. IL-7 is currently used as a cytokine therapy in HIV infection. We investigated whether the polymorphisms of the IL-7/IL-7RA genes were associated with disease progression.

Methods:  We have exhaustively genotyped the IL-7 and IL-7RA genes in the AIDS Genetics of Resistance to Immunodeficiency Virus (GRIV) cohort and in 370 healthy controls. The GRIV cohort involves 90 rapid progressors, i.e. patients with progression to CD4 <300/µL less than 3 years following seroconversion, and 280 slow progressors, i.e. asymptomatic subjects with CD4 >500/µL for more than 8 years after diagnosis of seropositivity. IL-7 gene was analyzed by polymerase chain reaction (PCR) and sequencing. IL-7RA gene was analyzed with the SNPlex method based on HapMap derived tagSNP. Statistical analyses were performed by the Fisher’s exact test by comparing either rapid or slow progressors with healthy controls.

Results:  We identified 28 SNP by genotyping the IL-7 gene, and we determined 9 tagSNP covering the 50 HapMap SNP known for IL-7RA. No association was detected in slow progressors, neither at the level of individual SNP nor at the level of haplotypes. In rapid progressors, weak positive signals (P comprised within 0.02 to 0.05) were found for 3 intronic SNP of IL-7 and a stronger signal was found for 1 intronic IL-7RA tagSNP (p = 0.007). No signal was detected in the single promoter SNP found for IL-7 nor in the single 1 present in IL-7RA. No exonic SNP was found for IL-7, however we could haplotype the combinations of tagSNP corresponding to the 4 known exonic variants of IL-7RA. A strong signal (p = 0.009) was found for the combination Ile244Thr and Val356Ile, i.e. the haplotype 244Thr/356Ile was found more prevalent in the recessive mode among rapid progressors (32.7%) than in healthy controls (16.9%) or in slow progressors (20.4%).

Conclusions:  Our preliminary study points out a protein risk allele of IL-7RA for rapid progression to AIDS. Interestingly, the 244 variant identified here is a major risk factor for another immune-related disease, namely multiple sclerosis, as recently described in a genome-wide. Further studies in other HIV cohorts and functional analysis of these variants must be performed to confirm this hypothesis and to understand their effect on immune regulation.