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. 2019 Apr 12;9(1):5963.
doi: 10.1038/s41598-019-41588-1.

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  1 , Patrick Haslett  2 , Barbara Sherry  3   4 , David H Shepp  1 , Paul Barber  5 , Jonathan Abshier  6 , Upal Roy  7 , Helena Schmidtmayerova  8
Affiliations

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 et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Plasma levels of the TH2 chemokine CCL18 are significantly increased in HIV-1 infected patients. CCL18 levels were analyzed by ELISA in plasma samples collected from the blood of 44 HIV-1 infected patients (irrespective of treatment status) and 51 control individuals (cohort 1). P value was calculated by a t-test.
Figure 2
Figure 2
Plasma levels of CCL18 correlate with viral load in the group of untreated HIV-1-infected patients. (a) Regression analysis of the correlation between plasma CCL18 levels detected in the group of untreated HIV-1 infected patients and HIV-1 mRNA copies detected in plasma isolated from the same patients (b) Regression analysis of the correlation between CCL18 levels detected in all HIV-1 infected patients (regardless of treatment status) and HIV-1 mRNA copies detected in plasma isolated from the same patients. (c) CCL18 levels detected in plasma isolated from 21 untreated and 23 cART-treated HIV-1-infected patients. All samples are from cohort 1. P value was calculated by a t-test.
Figure 3
Figure 3
Plasma levels of CCL18 negatively correlate with CD4+ T cell counts in HIV-1 infected patients. CCL18 levels were analyzed by ELISA in plasma samples collected from 68 HIV-1 infected patients on cART with undetectable plasma viral load (cohort 2). The CD3+CD4+ and CD3+CD8+ cell counts and the expression of CD38 on both cell populations were determined by flow cytometry. Correlation of CCL18 levels with (a) CD3+CD8+CD38+ cells, (b) CD3+CD4+ CD38+ cells, (c) CD3+CD8+ cell count, (d) CD3+CD4+ cell count, and (e) CD4/CD8 ratio was determined by Spearman Correlation Coefficients using SAS software. (f) Cohort 2 CCL18 levels detected in the plasma of 68 HIV-1-infected patients on cART with undetectable plasma viral load as compared to control individuals.
Figure 4
Figure 4
Plasma levels of the Th2 chemokines CCL17 and CCL22 in HIV-1 infected patients. CCL17 and CCL22 were analyzed by ELISA in plasma collected from 68 HIV-1-infected patients on cART with undetectable plasma viral load and compared to those detected in healthy controls. Upper panels show plasma levels of CCL17 (a), and correlation of plasma CCL17 levels with CD3+CD4+ (b) and CD3+CD4+ CD38+ (c) positive cells. Lower panels show plasma levels of CCL22 (d), and their correlation with CD3+CD4+ (e) and CD3+CD4+ CD38+ (f) positive cells. All samples are from cohort 2. P values were calculated using t-test.
Figure 5
Figure 5
In vitro analysis of the CD4+ T cell population cultivated in the presence of CCL18. (a) Representative staining of CD4+ lymphocytes cultivated with human recombinant CCL18 (500 ng/ml) and activated with CD3/CD28, CD3, or IL-2. Control shows staining of activated lymphocytes cultivated without CCL18. In parallel, cells were stained with mouse isotype antibody (Iso) to rule out non-specific binding. (b) Percent of CD4+ T cells in lymphocytes cultivated with or without CCL18 as described above. Data show results of one representative experiment out of three, each performed in duplicate.
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