Myeloid Derived Suppressor Cells Expansion Persists After Early ART and May Affect CD4 T Cell Recovery

Chiara Agrati,Patrizia Lorenzini,Andrea Sabatini,Eleonora Cimini,Alessandra Amendola,Carmela Pinnetti,Alessandra Sacchi,Veronica Bordoni,Germana Grassi,Isabella Abbate,Rita Casetti,Annalisa Mondi,Andrea Antinori,Nicola Tumino

doi:10.3389/fimmu.2019.01886

Abstract

Myeloid-derived suppressor cells (MDSC) are expanded during HIV-1 infection and correlated with disease progression. MDSC expand in the early phase of primary infection depending on TRAIL level. In this study we evaluated the effect of ART on the frequency of MDSC in patients with primary HIV infection (PHI), and their impact on CD4 T cell reconstitution. MDSC frequency was evaluated by flow-cytometry in 60 PHI patients at 12, 24 and 48 weeks after ART initiation. Cytokine plasma levels were evaluated by Luminex technology at the same time points. The capacity of MDSC to modulate hematopoietic early progenitor cells' expansion was evaluated using the OP9/Dl1 in vitro system. As previously described, polymorphonuclear-MDSC (PMN-MDSC) frequency was higher in PHI compared to healthy donors. Interestingly, 48 weeks of successful ART failed to normalize the PMN-MDSC frequency. Moreover, PMN-MDSC frequency was not correlated with residual viral load, suggesting that the persistence of PMN-MDSC was not due to residual viral replication. Interestingly, patients with low PMN-MDSC frequency (<6%) at T0 had a higher HIV DNA at the same time point than individuals with high PMN-MDSC frequency (>6%). We also found an inverse correlation between PMN-MDSC frequency and CD4-T cell count at 48 weeks post-ART, which was confirmed by multivariate analysis adjusting for age and CD4 T cell number at baseline. These data suggest that the persistence of PMN-MDSC may impact CD4 T cell recovery. Indeed, in vitro PMN-MDSC impaired the expansion of CD34+CD38- hematopoietic early progenitors. Further, a balance between TRAIL and GM-CSF may be necessary to maintain a low MDSC level. In conclusion, early ART initiation was not able to normalize PMN-MDSC frequency that might impact the CD4 T cell recovery. These data open new questions regarding the clinical impact of MDSC persistence in HIV+ patients, in particular on non-AIDS related diseases.

Highlights

Several conditions associated with various types of chronic inflammation result in aberrant and sustained myelopoiesis, characterized by the accumulation of myeloid cells with regulatory functions and defined as myeloid-derived suppressor cells (MDSC) [1,2,3]
Because of the high variability of PMN-MDSC frequency in primary HIV infection (PHI), we grouped patients based on PMN-MDSC frequency at T0: low PMN-MDSC group (6%); we decided to use the 6% cut off since it represented the highest PMN-MDSC frequency found in the HD group
In line with these results, we demonstrated that PMN-MDSC frequency of PHI patients remained stably higher than HD during therapy

Summary

Introduction

Several conditions associated with various types of chronic inflammation result in aberrant and sustained myelopoiesis, characterized by the accumulation of myeloid cells with regulatory functions and defined as myeloid-derived suppressor cells (MDSC) [1,2,3]. MDSC are able to inhibit a broad range of immune cell functions such as T cell proliferation and activation [8, 9], cytokine production by macrophages [10], and NK cell function [11]. They are involved in the induction of regulatory T cells [12], playing a pivotal role in regulating immune response. We observed the spread of suppressive PMN-MDSC in the acute phase of HIV infection [17], in particular in the first Fiebig stages. The aim of the present work was to better understand the dynamic of MDSC during ART started in the early phase of HIV infection and the possible impact of their persistence on immune reconstitution

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