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.

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients

“…Among the cases, 226 could be classified for the immune recovery study: 118 participants had more than 250 CD4 + Tcells/mL after 48 weeks of ART ("immunological responders", IRs), and 108 participants did not reach the 250 cells/mL CD4 + T-cell threshold ("immunological nonresponders", INRs). The threshold of 250 CD4+T-cells/mL to classify patients regarding immune recovery status was previously validated by the fact that patients receiving cART with CD4 + T-cells persistently below 250 cells/mL area associated with worse clinical outcomes [5] and thus, to be consistent with our previous related work, [10] in this study we maintain the same threshold criteria.…”

“…In fact, the connection between the expression of different proinflammatory cytokines and the discordant response encouraged us to recently explore the role of the IL-7/IL-7R axis in INRs. [10] Since our results confirmed that improved knowledge of this cytokine and its receptor in HIV participants could produce new insights regarding the immune response to ART, we hypothesized that the study of some selected chemokines related to IL-7/IL-7R axis could help to identify the molecular mechanisms associated with immune dysregulation preceding a discordant response to ART. Thus, in this study, we evaluated circulating baseline (pre-ART) and 48-week follow-up concentrations of stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12) (SDF-1/CXCL12), fractalkine/ CX3CL1, monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 alpha (MIP-a/CCL3), macrophage inflammatory protein-1 beta (MIP-b/CCL4) and RANTES (regulated upon activation, normal T cell expressed and secreted), also known as CCL5, and we also determined whether some selected CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) are associated with CD4 + T-cell recovery in a previously characterized cohort of HIV participants.…”

“…Thus, in this study, we evaluated circulating baseline (pre-ART) and 48-week follow-up concentrations of stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12) (SDF-1/CXCL12), fractalkine/ CX3CL1, monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 alpha (MIP-a/CCL3), macrophage inflammatory protein-1 beta (MIP-b/CCL4) and RANTES (regulated upon activation, normal T cell expressed and secreted), also known as CCL5, and we also determined whether some selected CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) are associated with CD4 + T-cell recovery in a previously characterized cohort of HIV participants. [10] 2. MATERIALS AND METHODS…”

“…A multicentre, longitudinal case-controlled study of 502 adult HIV-positive participants who were consecutively recruited between 2011 and 2013 at the HIV outpatient clinics of the participating hospitals who started their first ART and achieved virological suppression after ART was performed. [10] Patients were selected from among those who were receiving a combination of two nucleoside reverse transcriptase inhibitors (NRTI) plus a nonnucleoside reverse transcriptase inhibitor (NNRTIs) or a protease inhibitor(s) (PI). A flowchart of patient selection and enrolment is provided in Fig.…”

“…1 with the previously defined inclusion/exclusion criteria. [10] Of the selected patients, 262 were defined as controls (baseline CD4 + T-cell counts >200 cells/mL), and 240 were cases (baseline CD4 + T-cell counts 200 cells/mL). Among the cases, 226 could be classified for the immune recovery study: 118 participants had more than 250 CD4 + Tcells/mL after 48 weeks of ART ("immunological responders", IRs), and 108 participants did not reach the 250 cells/mL CD4 + T-cell threshold ("immunological nonresponders", INRs).…”