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

McCausland MR, Juchnowski SM, Zidar DA, Kuritzkes DR, Andrade A, Sieg SF, Lederman MM, Funderburg NT - PLoS ONE (2015)

Bottom Line: Monocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined.We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls.In 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.

ABSTRACT

Background: Monocytes 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.

Methods: Cryopreserved 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.

Results: In 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.

Conclusions: In 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.

No MeSH data available.


Related in: MedlinePlus

Expression and density (MFI) of CCR2 on patient monocytes at baseline and after ART initiation compared to values among controls.Values for frequency and density of CCR2 on monocyte subsets in untreated HIV-1 infection were compared to levels among controls using Mann Whitney U tests, and baseline values among patients were compared to values after ART initiation using GEE and Signed Rank test (see boxed legend). Figures show boxplots of medians and interquartile ranges; outliers are shown as open circles. Tukey boxplots show the proportion of CCR2+ total monocytes (A), traditional monocytes (C), inflammatory monocytes (E), and patrolling monocytes (G) in control samples (red) and in patient samples at baseline and after ART initiation. Tukey boxplots show the density of CCR2 on total monocytes (B), traditional monocytes (D), inflammatory monocytes (F), and patrolling monocytes (H) in control samples (red) and in patient samples at baseline and after ART initiation.
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pone.0139474.g005: Expression and density (MFI) of CCR2 on patient monocytes at baseline and after ART initiation compared to values among controls.Values for frequency and density of CCR2 on monocyte subsets in untreated HIV-1 infection were compared to levels among controls using Mann Whitney U tests, and baseline values among patients were compared to values after ART initiation using GEE and Signed Rank test (see boxed legend). Figures show boxplots of medians and interquartile ranges; outliers are shown as open circles. Tukey boxplots show the proportion of CCR2+ total monocytes (A), traditional monocytes (C), inflammatory monocytes (E), and patrolling monocytes (G) in control samples (red) and in patient samples at baseline and after ART initiation. Tukey boxplots show the density of CCR2 on total monocytes (B), traditional monocytes (D), inflammatory monocytes (F), and patrolling monocytes (H) in control samples (red) and in patient samples at baseline and after ART initiation.

Mentions: We next examined the distribution of the chemokine receptors CCR2 and CX3CR1 on monocyte subsets (Figs 5 and 6). As expected, traditional monocytes had the highest expression of CCR2 and the lowest expression of CX3CR1, and, conversely, patrolling monocytes had the highest expression of CX3CR1 and the lowest expression of CCR2, with expression of these molecules on inflammatory monocytes falling in between[23].


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

McCausland MR, Juchnowski SM, Zidar DA, Kuritzkes DR, Andrade A, Sieg SF, Lederman MM, Funderburg NT - PLoS ONE (2015)

Expression and density (MFI) of CCR2 on patient monocytes at baseline and after ART initiation compared to values among controls.Values for frequency and density of CCR2 on monocyte subsets in untreated HIV-1 infection were compared to levels among controls using Mann Whitney U tests, and baseline values among patients were compared to values after ART initiation using GEE and Signed Rank test (see boxed legend). Figures show boxplots of medians and interquartile ranges; outliers are shown as open circles. Tukey boxplots show the proportion of CCR2+ total monocytes (A), traditional monocytes (C), inflammatory monocytes (E), and patrolling monocytes (G) in control samples (red) and in patient samples at baseline and after ART initiation. Tukey boxplots show the density of CCR2 on total monocytes (B), traditional monocytes (D), inflammatory monocytes (F), and patrolling monocytes (H) in control samples (red) and in patient samples at baseline and after ART initiation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591977&req=5

pone.0139474.g005: Expression and density (MFI) of CCR2 on patient monocytes at baseline and after ART initiation compared to values among controls.Values for frequency and density of CCR2 on monocyte subsets in untreated HIV-1 infection were compared to levels among controls using Mann Whitney U tests, and baseline values among patients were compared to values after ART initiation using GEE and Signed Rank test (see boxed legend). Figures show boxplots of medians and interquartile ranges; outliers are shown as open circles. Tukey boxplots show the proportion of CCR2+ total monocytes (A), traditional monocytes (C), inflammatory monocytes (E), and patrolling monocytes (G) in control samples (red) and in patient samples at baseline and after ART initiation. Tukey boxplots show the density of CCR2 on total monocytes (B), traditional monocytes (D), inflammatory monocytes (F), and patrolling monocytes (H) in control samples (red) and in patient samples at baseline and after ART initiation.
Mentions: We next examined the distribution of the chemokine receptors CCR2 and CX3CR1 on monocyte subsets (Figs 5 and 6). As expected, traditional monocytes had the highest expression of CCR2 and the lowest expression of CX3CR1, and, conversely, patrolling monocytes had the highest expression of CX3CR1 and the lowest expression of CCR2, with expression of these molecules on inflammatory monocytes falling in between[23].

Bottom Line: Monocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined.We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls.In 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.

ABSTRACT

Background: Monocytes 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.

Methods: Cryopreserved 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.

Results: In 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.

Conclusions: In 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.

No MeSH data available.


Related in: MedlinePlus