Identification of IL7RA Risk Alleles for Rapid Progression During HIV-1 Infection: A Comprehensive Study in the GRIV Cohort

Sophie      Limou; Giovanna      Melica; Cedric      Coulonges; Jean-Daniel      Lelievre; Herve      Do; Steven      McGinn; Ivo      G. Gut; Yves      Levy; Jean-Francois      Zagury

Abstract

Interleukin 7 (IL7) is a critical factor for lymphocyte homeostasis. A dysfunction of the IL7/IL7R pathway has previously been described in HIV-1 infection, and promising results were observed in recent analyses of IL7 for therapeutic use in HIV infected individuals. However, further investigations are still warranted to understand the possible roles of this cytokine. Here, we explored whether the IL7 and IL7RA genetic polymorphisms were associated with the progression of HIV infection. We extensively genotyped the IL7 and IL7RA genes in the GRIV (Genomics of Resistance to Immunodeficiency Virus) cohort, composed of patients with extreme progression profiles - long-term non (LTNP) and rapid (RP) progressors -, and in a healthy control group (CTR). Statistical case-control analyses were performed using the Fisher’s exact test, comparing either LTNP vs CTR or RP vs CTR. Three IL7RA SNPs (single nucleotide polymorphisms - rs7701176, rs987106 and rs10491434), but no IL7 SNPs, were significantly associated with rapid disease progression (P<0.01). In a multi-marker analysis focusing on functional variants, a strong association between an IL7RA haplotype and rapid progression was observed (P=5.59x10-3). In summary, our comprehensive genetic study revealed three SNPs and a risk of haplotype associated with rapid progression to AIDS in the IL7RA gene. Interestingly, the haplotype is composed of SNPs previously identified in other inflammatory diseases (e.g., multiple sclerosis) by GWAS and by functional studies. Our results contribute to the growing understanding of the role of IL7/IL7R in HIV disease progression, and more widely, in CD4+ T cell homeostasis.

Keywords: Genetic association study, haplotype, HIV, IL7RA, rapid progression, SNP, T cell homeostasis

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