High Plasma Levels of sTNF-R1 and CCL11 Are Related to CD4+ T-Cells Fall in Human Immunodeficiency Virus Elite Controllers With a Sustained Virologic Control.

Mónica Gutiérrez-Rivas,Clara Restrepo,Norma Rallón,Juan González-García,María Ángeles Jiménez-Sousa,Marta Montero-Alonso,María Ángeles Muñoz-Fernández,Salvador Resino,José Luis Jiménez,José Miguel Benito,Agathe León

doi:10.3389/fimmu.2018.01399

Abstract

Our aim was to analyze the relationship between plasma inflammatory biomarkers and CD4+ T-cells evolution in human immunodeficiency virus (HIV) elite controllers (HIV-ECs) with a suppressed viremia. We carried out a retrospective study in 30 HIV-ECs classified into two groups: those showing no significant loss of CD4+ T-cells during the observation period (stable CD4+, n = 19) and those showing a significant decrease of CD4+ T-cells (decline CD4+, n = 11). Baseline plasma biomarkers were measured using a multiplex immunoassay: sTNF-R1, TRAIL, sFas (APO), sFasL, TNF-α, TNF-β, IL-8, IL-18, IL-6, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, SDF1α, GRO-α, and CCL11. Baseline levels of sTNF-R1 and CCL11 and sTNF-R1/TNF-α ratio correlated with the slope of CD4+ T-cells (cells/μl/year) during follow-up [r = −0.370 (p = 0.043), r = −0.314 (p = 0.091), and r = −0.381 (p = 0.038); respectively]. HIV-ECs with declining CD4+ T-cells had higher baseline plasma levels of sTNF-R1 [1,500.7 (555.7; 2,060.7) pg/ml vs. 450.8 (227.9; 1,263.9) pg/ml; p = 0.018] and CCL11 [29.8 (23.5; 54.9) vs. 19.2 (17.8; 29.9) pg/ml; p = 0.041], and sTNF-R1/TNF-α ratio [84.7 (33.2; 124.2) vs. 25.9 (16.3; 75.1); p = 0.012] than HIV-1 ECs with stable CD4+ T-cells. The area under the receiver operating characteristic (ROC) curve [area under ROC curve (AUROC)] were 0.758 ± 0.093 (sTNF-R1), 0.727 ± 0.096 (CCL11), and 0.777 ± 0.087 (sTNF-R1/TNF-α). The cut-off of 75th percentile (high values) for these biomarkers had 71.4% positive predictive value and 73.9% negative predictive value for anticipating the evolution of CD4+ T-cells. In conclusion, the loss of CD4+ T-cells in HIV-ECs was associated with higher levels of two plasma inflammatory biomarkers (sTNF-R1 and CCL11), which were also reasonably accurate for the prediction of the CD4+ T-cells loss.

Highlights

CD4+ T-cells are the major target for human immunodeficiency virus (HIV); a gradual CD4+ T-cells count decline and progression to acquired immune deficiency syndrome (AIDS) are normally observed during untreated HIVinfection [1]
We found a relationship of two plasma inflammatory biomarkers with the CD4+ slopes during the long-term control of HIV replication in our cohort of HIV elite controllers (HIV-ECs)
The immune activation is a hallmark of HIV-1 disease and the role of immune activation in HIV-1 pathogenesis and immune dysfunction is recognized [15]

Summary

Introduction

CD4+ T-cells are the major target for human immunodeficiency virus (HIV); a gradual CD4+ T-cells count decline and progression to acquired immune deficiency syndrome (AIDS) are normally observed during untreated HIVinfection [1]. Most patients have elevated CD4+ T-cells count, stable CD4+ T-cell trajectories, and more favorable clinical outcomes compared with viremic patients; but a subgroup of HIV-ECs may progress to AIDS with CD4+ T-cells decline and/or loss of virologic control [4] In this regard, HIV-ECs showed lower marker levels of inflammatory and immune activation than HIV viremic controllers (HIV-VCs) [5, 6]. Chronic immune activation associated with HIV infection may lead to fibrosis in the lymphoid tissues, where HIV replicates, for dramatically altering the structure and function, giving rise to a progressive loss of CD4+ T-cells, in the naive T-cells subset [11, 12] In this regard, HIV-ECs have significant lymphoid tissue fibrosis and CD4+ T-cells depletion at lymphoid tissue, similar to HIV non-controllers [13]

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