IL-7/IL-7R gene variants impact circulating IL-7/IL-7R homeostasis and ART-associated immune recovery status

Abstract

A relationship between polymorphisms in genes encoding interleukin 7 (IL-7) and its cellular receptor (IL-7R) and antiretroviral therapy (ART)-associated immune recovery in HIV subjects has been previously reported. However, details of this relationship remain unclear, and the association of these polymorphisms with circulating IL-7/IL-7R levels is scarce. Here, we explored whether IL-7/IL-7R axis was associated with quantitative CD4⁺ T-cell recovery in HIV-infected subjects. IL-7/IL-7R polymorphisms were assessed by genotyping, and multiple inheritance models were used to estimate both, their association with low pre-ART CD4⁺ T-cell counts and incomplete immune recovery status after 48 weeks of suppressive ART. Integrated data from genetic variants association and soluble plasma IL-7/IL-7R quantification suggest that IL-7/IL-7R genotype expression could alter the homeostatic balance between soluble and membrane-bound receptors. The haplotype analyses indicates that allele combinations impacts pre-ART circulating CD4⁺ T-cell counts, immune recovery status and the absolute increment of CD4⁺ T-cell counts. The knowledge about how IL-7/IL-7R axis is related to quantitative CD4⁺ T-cell recovery and immune recovery status after initiating ART could be useful regarding T-cell reservoirs investigations in HIV subjects.

Figure 1

Flow chart illustrating subject cohort enrolment and analysis. HIV-infected subjects were included and categorized into controls and cases according to pre-ART CD4⁺ T-cell counts. For an immune recovery substudy group, cases starting ART with T-cell counts below 200 cells/µL were categorized according to their immune status after 48 weeks of follow-up.

Figure 2

Haplotype analysis for the IL-7R gene variants explored in this study. (A) Linkage disequilibrium (LD) analysis in INR subjects compared to IR subjects for IL-7R gene variants. (B) Haplotype association with immune recovery status according to CD4⁺ T-cell counts after 48 weeks of ART (n = 197).

Figure 3

Influence of IL-7R genes in circulating concentrations of IL-7R. Rs987106, rs3194051 and rs10491434 variants influence circulating plasma concentrations in IR subjects. Data are represented as the mean ± SD (65 INRs and 75 IRs). The relationship between IL-7R genes and plasma IL-7 concentrations were analyzed using one-way ANOVA test (SPSS software).

Figure 4

Impact of IL-7/IL-7R axis on the absolute increment of CD4+ T-cell counts. (A) Flow chart illustrating classification criteria according the absolute increment of CD4+ T-cell counts (ΔCD4+ T-cell) after 48 weeks of ART. (B) ΔCD4⁺ T-cell count mean ± SD values in cases2 and controls2 according to this classification criterion (n = 416). (C) Haplotype association with the ΔCD4+ T-cell count (n = 452). (D) Pre-ART circulating concentrations of IL-7 (n = 356) and IL-7R (n = 349) according ΔCD4+ T-cell count criteria. Data are represented as the mean ± SD. Comparisons between groups were performed with nonparametric Mann-Whitney (MW) (SPSS software).

Figure 5

Longitudinal evaluation of the IL-7/IL-7R axis during 144 weeks of ART. (A) Longitudinal study of circulating IL-7 and IL-7R values in the cases and the controls during 144 weeks of ART. (B) Longitudinal study of circulating IL-7 and IL-7R values in subjects classified according to the ΔCD4+ T-cell count criterion during 144 weeks of ART. Data are represented as the mean ± SEM Comparisons between groups were performed with nonparametric Mann-Whitney (MW) tests for unpaired samples and a Wilcoxon t-test for paired samples (W) (SPSS software).