Increased Bone Marrow Interleukin-7 (IL-7)/IL-7R Levels but Reduced IL-7 Responsiveness in HIV-Positive Patients Lacking CD4+ Gain on Antiviral Therapy

Giusi Maria Bellistrì,Giulia Marchetti,Giulio Ferrario,Anna Casabianca,Mauro Magnani,Chiara Orlandi,Luca Meroni,Antonella D'Arminio Monforte,Esther Merlini,Massimo Galli

doi:10.1371/journal.pone.0015663

Giusi Maria Bellistrì, Giulia Marchetti + Show 8 more

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https://doi.org/10.1371/journal.pone.0015663

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Abstract

BackgroundThe bone marrow (BM) cytokine milieu might substantially affect T-lymphocyte homeostasis in HIV-positive individuals. Interleukin-7 (IL-7) is a bone marrow-derived cytokine regulating T-cell homeostasis through a CD4+-driven feedback loop. CD4+ T-lymphopenia is associated with increased free IL-7 levels and reduced IL-7R expression/function, which are only partially reverted by highly active antiretroviral therapy (HAART). We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Rα in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ ≤200/µl) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA≤50), 12 complete failures (CFs; HIV-RNA>1000), and 23 HIV-seronegative subjects.MethodsWe studied plasma IL-7 levels, IL-7Rα+CD4+/CD8+ T-cell proportions, IL-7Rα mRNA expression in PBMCs, spontaneous IL-7 production by BM mononuclear cells (BMMCs), and IL-7 mRNA/IL-7Rα mRNA in BMMC-derived stromal cells (SCs). We also studied T-cell responsiveness to IL-7 by measuring the proportions of pStat5+ and Bcl-2+ CD4+/CD8+ T cells.ResultsCompared to HIV-seronegative controls, CFs and INRs presented elevated plasma IL-7 levels and lower IL-7Rα CD4+/CD8+ cell-surface expression and peripheral blood production, confirming the most relevant IL-7/IL-7R disruption. Interestingly, BM investigation revealed a trend of higher spontaneous IL-7 production in INRs (p = .09 vs. CFs) with a nonsignificant trend toward higher IL-7-Rα mRNA levels in BMMC-derived stromal cells. However, upon IL-7 stimulation, the proportion of pStat5+CD4+ T cells did not increase in INRs despite higher constitutive levels (p = .06); INRs also displayed lower Bcl-2+CD8+ T-cell proportions than controls (p = .04).ConclusionsDespite severe CD4+ T-lymphopenia and a disrupted IL-7/IL-7R profile in the periphery, INRs display elevated BM IL-7/IL-7Rα expression but impaired T-cell responsiveness to IL-7, suggesting the activity of a central compensatory pathway targeted to replenish the CD4+ compartment, which is nevertheless inappropriate to compensate the dysfunctional signaling through IL-7 receptor.

Highlights

Interleukin-7 (IL-7) is a type-1 stromally produced cytokine that plays a crucial role for T cell biology, enhancing thymocyte production [1,2], ‘‘homeostatic’’ proliferation, survival of memory and naıve peripheral T cells [3,4], type-1 immune responses and CD8+ T-cell cytotoxicity [5]
Aside from the immunodestructive effects of HIV-1, a major cause of the failure of IL-7 to sustain peripheral Tlymphocyte homeostasis might be the down-regulation of IL-7Rca expression and suppression of IL-7Ra function on peripheral T lymphocytes [9,10,11], which might counteract the positive effect of IL-7 on T-cell homeostasis
No differences were shown with respect to highly active antiretroviral therapy (HAART) regimen and duration between the groups; 83% of the patients (25/30) were on a protease inhibitor (PI)-based regimen (Table 1)

Summary

Introduction

Interleukin-7 (IL-7) is a type-1 stromally produced cytokine that plays a crucial role for T cell biology, enhancing thymocyte production [1,2], ‘‘homeostatic’’ proliferation, survival of memory and naıve peripheral T cells [3,4], type-1 immune responses and CD8+ T-cell cytotoxicity [5]. The IL-7/IL-7R axis has been shown to be crucial in sustaining peripheral T-cell homeostasis via a rise in circulating IL-7 levels that acts as a survival signal to both lymphoid progenitors and mature circulating T lymphocytes [7,8]. In line with this model, CD4+ T-lymphopenia in the course of HIV disease is characterized by a substantial increase in IL-7 plasma levels, and yet such an IL-7-enriched milieu fails to preserve the peripheral T-cell pool. We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Ra in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ #200/ml) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA#50), 12 complete failures (CFs; HIV-RNA.1000), and 23 HIVseronegative subjects

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