Increased Plasma Levels of the TH2 chemokine CCL18 associated with low CD4+ T cell counts in HIV-1-infected Patients with a Suppressed Viral Load

Prashant Malhotra,Barbara Sherry,Patrick Haslett,David H Shepp,Upal Roy,Paul Barber,Helena Schmidtmayerova,Jonathan Abshier

doi:10.1038/s41598-019-41588-1

Abstract

The chemokine (C-C motif) chemokine ligand 18 (CCL18) is a structural homolog of CCL3 primarily produced by monocyte-derived cells with an M2 phenotype. Elevated levels of CCL18 have been observed in several diseases associated with malignancies and chronic inflammation. The role of CCL18 in Human Immunodeficiency Virus (HIV-1) infection remains unknown. We analyzed expression levels of T helper cell-mediated (TH2) chemokines CCL18, CCL17, and CCL22 by ELISA in plasma collected from HIV-1-infected and healthy donors. In HIV-1-infected individuals, plasma viral loads were monitored by NucliSense HIV-1 QT assay and T cell counts and expression of the activation marker CD38 were determined by flow cytometry. Our data showed a significant increase in plasma levels of CCL18 in HIV-1-infected individuals compared to uninfected controls (p < 0.001) and a significant correlation between CCL18 levels and viral load in untreated patients. No significant difference of CCL18 levels was detected among the HIV-1-infected patients treated with combined antiretroviral therapy (cART) and HIV-1-untreated patients.CCL18 values are negatively correlated with CD4+CD38+ cell numbers and total CD4+ T cell counts in patients with a suppressed viral load. Notably, plasma levels of the TH2 chemokines CCL17 and CCL22 are also elevated during HIV-1 infection. However, no correlation of CCL17 and CCL22 production with CD4+ T cell counts was detected. Presented data shows that the chemokines, CCL17, CCL18, and CCL22 are increased during HIV-1 infection. However, only increased levels of CCL18, a marker of M2 macrophages, correlate with low CD4+ T cell counts in patients with suppressed viral load, raising the possibility that CCL18 and/or CCL18-producing cells may interfere with their reconstitution in HIV-1-infected patients on cART.

Highlights

HIV-1 infection is characterized by a complex immune disorder that presents itself as a decrease in CD4+ T cells, chronic immune activation, and imbalanced cytokine and chemokine production and macrophage dysfunction[1]
We focused on the TH2 chemokine CCL18, which is a marker of M2 macrophages and has been previously linked to several TH2 related pathological conditions[21]
The present study demonstrates that CCL18 levels are significantly increased in HIV-1-infected patients and correlate with viral load in the group of untreated patients

Summary

Introduction

HIV-1 infection is characterized by a complex immune disorder that presents itself as a decrease in CD4+ T cells, chronic immune activation, and imbalanced cytokine and chemokine production and macrophage dysfunction[1]. Inflammatory chemokines, which are induced or up-regulated by inflammation, play a role in attracting immune cells to sites of infection and inflammation[7]. Active CCL18 is constitutively expressed in plasma of healthy individuals[11] and levels are further increased under certain pathological conditions. Monocyte/macrophages constitutively express low levels of CCL18 and its expression is up-regulated by the TH2 cytokines IL-4, IL-10, and IL-1313,14. CCL18 triggers biological responses in target cells and induces migration of T cells[13], B cells[17], and macrophages[18] via CCL18 receptor CCR819. We report that plasma levels of CCL18 are significantly increased during HIV-1 infection and negatively correlate with CD3+CD4+ T cell counts in patients on combination antiretroviral therapy (cART) with a suppressed viral load

Methods

Results

Conclusion