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Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection.

Jost S, Moreno-Nieves UY, Garcia-Beltran WF, Rands K, Reardon J, Toth I, Piechocka-Trocha A, Altfeld M, Addo MM - Retrovirology (2013)

Bottom Line: Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells.Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals.In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA.

ABSTRACT

Background: Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.

Results: We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.

Conclusions: Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

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High plasma Galectin-9 concentration in early HIV-1 infection. (A) Dot plots represent the logarithmic concentration of soluble Gal-9 in the plasma of 9 healthy individuals, 11 subjects with early untreated HIV-1 infection, 15 with HAART-treated HIV-1 infection, and 47 untreated individuals with chronic HIV-1 infection, including 16 viremic controllers (blue), 15 elite controllers (green), and 16 subjects with chronic untreated progressive HIV-1 infection (red), as determined by ELISA. (B) Positive correlation between the logarithmic viral load and the logarithmic concentration of soluble Gal-9 in the plasma of 73 HIV-1 individuals, including 11 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. (C) Inverse correlation between the CD4+ T cell counts and the concentration of soluble Gal-9 in the plasma of 69 HIV-1 individuals, including 7 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. CD4-T cell counts were not available for 4 subjects with early HIV-1 infection at the exact date of the sample draw.
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Figure 2: High plasma Galectin-9 concentration in early HIV-1 infection. (A) Dot plots represent the logarithmic concentration of soluble Gal-9 in the plasma of 9 healthy individuals, 11 subjects with early untreated HIV-1 infection, 15 with HAART-treated HIV-1 infection, and 47 untreated individuals with chronic HIV-1 infection, including 16 viremic controllers (blue), 15 elite controllers (green), and 16 subjects with chronic untreated progressive HIV-1 infection (red), as determined by ELISA. (B) Positive correlation between the logarithmic viral load and the logarithmic concentration of soluble Gal-9 in the plasma of 73 HIV-1 individuals, including 11 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. (C) Inverse correlation between the CD4+ T cell counts and the concentration of soluble Gal-9 in the plasma of 69 HIV-1 individuals, including 7 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. CD4-T cell counts were not available for 4 subjects with early HIV-1 infection at the exact date of the sample draw.

Mentions: To further dissect the potential mechanisms leading to alterations in Tim-3 expression on NK cells, we examined whether differential plasma concentration or cellular expression of Gal-9, a Tim-3 ligand, accounts for the changes observed in early and chronic HIV-1 infection. Plasma Gal-9 levels were more than 6-times higher in late primary HIV-1 infection and twice higher in chronically infected HIV-1-positive subjects than in healthy controls (Figure 2A). There was no difference in soluble Gal-9 levels between HAART-treated and untreated subjects with progressive or controlled HIV infection. Likewise, the differences between HIV-negative and HIV-1-positive populations did not reach statistical significance. Elevated concentrations of Gal-9 in HIV-1-infected subjects were positively correlated with viremia (Figure 2B) and negatively correlated with CD4+ T-cell counts (Figure 2C).


Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection.

Jost S, Moreno-Nieves UY, Garcia-Beltran WF, Rands K, Reardon J, Toth I, Piechocka-Trocha A, Altfeld M, Addo MM - Retrovirology (2013)

High plasma Galectin-9 concentration in early HIV-1 infection. (A) Dot plots represent the logarithmic concentration of soluble Gal-9 in the plasma of 9 healthy individuals, 11 subjects with early untreated HIV-1 infection, 15 with HAART-treated HIV-1 infection, and 47 untreated individuals with chronic HIV-1 infection, including 16 viremic controllers (blue), 15 elite controllers (green), and 16 subjects with chronic untreated progressive HIV-1 infection (red), as determined by ELISA. (B) Positive correlation between the logarithmic viral load and the logarithmic concentration of soluble Gal-9 in the plasma of 73 HIV-1 individuals, including 11 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. (C) Inverse correlation between the CD4+ T cell counts and the concentration of soluble Gal-9 in the plasma of 69 HIV-1 individuals, including 7 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. CD4-T cell counts were not available for 4 subjects with early HIV-1 infection at the exact date of the sample draw.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750478&req=5

Figure 2: High plasma Galectin-9 concentration in early HIV-1 infection. (A) Dot plots represent the logarithmic concentration of soluble Gal-9 in the plasma of 9 healthy individuals, 11 subjects with early untreated HIV-1 infection, 15 with HAART-treated HIV-1 infection, and 47 untreated individuals with chronic HIV-1 infection, including 16 viremic controllers (blue), 15 elite controllers (green), and 16 subjects with chronic untreated progressive HIV-1 infection (red), as determined by ELISA. (B) Positive correlation between the logarithmic viral load and the logarithmic concentration of soluble Gal-9 in the plasma of 73 HIV-1 individuals, including 11 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. (C) Inverse correlation between the CD4+ T cell counts and the concentration of soluble Gal-9 in the plasma of 69 HIV-1 individuals, including 7 subjects with early infection, 16 viremic controllers, 15 elite controllers, 16 subjects with chronic untreated, and 15 with treated HIV-1 infection. CD4-T cell counts were not available for 4 subjects with early HIV-1 infection at the exact date of the sample draw.
Mentions: To further dissect the potential mechanisms leading to alterations in Tim-3 expression on NK cells, we examined whether differential plasma concentration or cellular expression of Gal-9, a Tim-3 ligand, accounts for the changes observed in early and chronic HIV-1 infection. Plasma Gal-9 levels were more than 6-times higher in late primary HIV-1 infection and twice higher in chronically infected HIV-1-positive subjects than in healthy controls (Figure 2A). There was no difference in soluble Gal-9 levels between HAART-treated and untreated subjects with progressive or controlled HIV infection. Likewise, the differences between HIV-negative and HIV-1-positive populations did not reach statistical significance. Elevated concentrations of Gal-9 in HIV-1-infected subjects were positively correlated with viremia (Figure 2B) and negatively correlated with CD4+ T-cell counts (Figure 2C).

Bottom Line: Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells.Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals.In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA.

ABSTRACT

Background: Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.

Results: We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.

Conclusions: Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

Show MeSH
Related in: MedlinePlus