Altered Monocyte Phenotype in HIV-1 Infection Tends to Normalize with Integrase-Inhibitor-Based Antiretroviral Therapy.

Marie R Mccausland,Nicholas T Funderburg,Daniel R Kuritzkes,Michael M Lederman,David A Zidar,Scott F Sieg,Steven M Juchnowski,Adriana Andrade,Alexandre Boissonnas

doi:10.1371/journal.pone.0139474

Abstract

BackgroundMonocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined. Here, we define more completely monocyte phenotype both prior to ART initiation and during 48 weeks of ART.MethodsCryopreserved peripheral blood mononuclear cells (PBMCs) were obtained at baseline (prior to ART initiation) and at weeks 12, 24, and 48 of treatment from 29 patients participating in ACTG clinical trial A5248, an open label study of raltegravir/emtricitibine/tenofovir administration. For comparison, cryopreserved PBMCs were obtained from 15 HIV-1 uninfected donors, each of whom had at least two cardiovascular risk factors. Thawed samples were stained for monocyte subset markers (CD14 and CD16), HLA-DR, CCR2, CX3CR1, CD86, CD83, CD40, CD38, CD36, CD13, and CD163 and examined using flow cytometry.ResultsIn untreated HIV-1 infection there were perturbations in monocyte subset phenotypes, chiefly a higher frequency and density (mean fluorescence intensity–MFI) of HLA-DR (%-p = 0.004, MFI-p = .0005) and CD86 (%-p = 0.012, MFI-p = 0.005) expression and lower frequency of CCR2 (p = 0.0002) expression on all monocytes, lower CCR2 density on inflammatory monocytes (p = 0.045) when compared to the expression and density of these markers in controls’ monocytes. We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls. After ART, these perturbations tended to improve, with decreasing expression and density of HLA-DR and CD86, increasing CCR2 density on inflammatory monocytes, and increasing expression and density of CX3CR1 on patrolling monocytes.ConclusionsIn HIV-1 infected patients, ART appears to attenuate the high levels of activation (HLA-DR, CD86) and to increase expression of the chemokine receptors CCR2 and CX3CR1 on monocyte populations. Circulating monocyte phenotypes are altered in untreated infection and tend to normalize with ART; the role of these cells in the inflammatory environment of HIV-1 infection warrants further study.

Highlights

Monocytes are increasingly recognized as contributors to inflammation and coagulation in HIV-1 infection [1,2,3]
We report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls
In HIV-1 infected patients, antiretroviral therapy (ART) appears to attenuate the high levels of activation (HLA-DR, CD86) and to increase expression of the chemokine receptors CCR2 and CX3CR1 on monocyte populations

Summary

Introduction

Monocytes are increasingly recognized as contributors to inflammation and coagulation in HIV-1 infection [1,2,3] These antigen-presenting cells can be segregated into three functionally distinct populations based on CD14 and CD16 expression [4, 5]. “Patrolling” monocytes (CD14dimCD16+) produce IL6 and IL8 in response to viral elements, and patrol the vascular endothelium [6] Increased proportions of both the inflammatory and patrolling monocytes have been reported previously in untreated HIV-1 infected patients when compared to the proportions in a healthy control population[1]. This nomenclature describes the function of these monocytes; others have characterized these cells as classical, intermediate and non-classical monocyte subsets respectively[5]. We define more completely monocyte phenotype both prior to ART initiation and during 48 weeks of ART

Methods

Results

Conclusion