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Toll-like receptor 3 signalling up-regulates expression of the HIV co-receptor G-protein coupled receptor 15 on human CD4+ T cells.

Kiene M, Rethi B, Jansson M, Dillon S, Lee E, Lantto R, Wilson C, Pöhlmann S, Chiodi F - PLoS ONE (2014)

Bottom Line: Here, we show that GPR15 expression in CD4(+) T cells is markedly up-regulated in some HIV-1 infected individuals compared to the rest of the infected patients and to healthy controls.Up-regulation of GPR15 expression on CD4(+) T cells was induced by activation of Toll-like receptor 3 signalling via TIR-domain-containing adapter-inducing interferon-β (TRIF) and was more prominent on gut-homing compared to lymph node-homing CD4(+) T cells.These results suggest that infection-induced up-regulation of GPR15 expression could increase susceptibility of CD4(+) T cells to HIV infection and target cell availability in the gut in some infected individuals.

View Article: PubMed Central - PubMed

Affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany ; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Background: Many HIV-2 and SIV isolates, as well as some HIV-1 strains, can use the orphan 7-transmembrane receptor GPR15 as co-receptor for efficient entry into host cells. GPR15 is expressed on central memory and effector memory CD4(+) T cells in healthy individuals and a subset of these cells is susceptible to HIV-1 and SIV infection. However, it has not been determined whether GPR15 expression is altered in the context of HIV-1 infection.

Results: Here, we show that GPR15 expression in CD4(+) T cells is markedly up-regulated in some HIV-1 infected individuals compared to the rest of the infected patients and to healthy controls. Infection of the PM1 T cell line with primary HIV-1 isolates was found to up-regulate GPR15 expression on the infected cells, indicating that viral components can induce GPR15 expression. Up-regulation of GPR15 expression on CD4(+) T cells was induced by activation of Toll-like receptor 3 signalling via TIR-domain-containing adapter-inducing interferon-β (TRIF) and was more prominent on gut-homing compared to lymph node-homing CD4(+) T cells.

Conclusion: These results suggest that infection-induced up-regulation of GPR15 expression could increase susceptibility of CD4(+) T cells to HIV infection and target cell availability in the gut in some infected individuals.

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Related in: MedlinePlus

GPR15 is mostly present on central memory CD4+Tcells in HIV-1 infected individuals and uninfected controls.PBMCs were isolated from whole blood by Lymphoprep gradient centrifugation and stained for CD3, CD4, CCR7, CD45RA and GPR15. (A) Cells were gated for lymphocytes, CD3+, CD4+ and CCR7+CD45RA− (CM: central memory), CCR7−CD45RA− (EM: effector memory) or CCR7+CD45RA+ (N: naïve) (A) and GPR15 expression on the subsets was analyzed via FACS (B). The GPR15 expression on CD4+ T cell subpopulations was analyzed in eight uninfected controls and eleven HIV-1 infected patients (C) as indicated in (A, B). GPR15 expression is shown as the percent of the analysed subpopulation which expresses the co-receptor (C). Blood samples taken two month later from the two high GPR15 expressing HIV-1 infected patients and two controls (shown in C) were stained for GPR15, CD4 and CD8 (D) or CD4 and other co-receptors like CXCR4, CCR5 and CXCR6 (E). The co-receptor expressions are shown as a percent of CD4+ and CD8+ T cells expressing GPR15 (D) or of CD4+ T cells expressing CXCR4, CCR5 or CXCR6 (E). Statistical analysis was done using Wilcoxon signed-rank test with GraphPad Prism.
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pone-0088195-g001: GPR15 is mostly present on central memory CD4+Tcells in HIV-1 infected individuals and uninfected controls.PBMCs were isolated from whole blood by Lymphoprep gradient centrifugation and stained for CD3, CD4, CCR7, CD45RA and GPR15. (A) Cells were gated for lymphocytes, CD3+, CD4+ and CCR7+CD45RA− (CM: central memory), CCR7−CD45RA− (EM: effector memory) or CCR7+CD45RA+ (N: naïve) (A) and GPR15 expression on the subsets was analyzed via FACS (B). The GPR15 expression on CD4+ T cell subpopulations was analyzed in eight uninfected controls and eleven HIV-1 infected patients (C) as indicated in (A, B). GPR15 expression is shown as the percent of the analysed subpopulation which expresses the co-receptor (C). Blood samples taken two month later from the two high GPR15 expressing HIV-1 infected patients and two controls (shown in C) were stained for GPR15, CD4 and CD8 (D) or CD4 and other co-receptors like CXCR4, CCR5 and CXCR6 (E). The co-receptor expressions are shown as a percent of CD4+ and CD8+ T cells expressing GPR15 (D) or of CD4+ T cells expressing CXCR4, CCR5 or CXCR6 (E). Statistical analysis was done using Wilcoxon signed-rank test with GraphPad Prism.

Mentions: We have previously reported that GPR15 is expressed on central memory and, to a lesser extent, on effector memory T cells while expression of this receptor on naïve T cells is absent [23]. To investigate whether GPR15 expression on these T cell subsets is altered in the context of HIV-1 infection, we analyzed surface expression of GPR15 on CCR7+CD45RA− central memory, CCR7−CD45RA− effector memory and CCR7+CD45RA+ naïve CD4+ T cells (Figures 1A and 1B) from healthy donors and HIV-1 infected individuals. In line with our previous results [23], GPR15 was expressed to a significantly higher level on central memory (7±2.4%) compared to effector memory (3.7±2.2%; p = 0.026) and naïve CD4+ T cells (no detectable expression) (p = 0.016) in non-infected controls. A similar expression pattern was observed for HIV-1 infected individuals (ART treated and non-treated individuals) (Figure 1C), with no significant differences when comparing the levels to the non-infected controls. Although a limited number of specimens obtained from ART naïve patients was used in the study, we could not find a significant difference in GPR15 expression whencomparing ART treated HIV-1 infected individuals to the non-treated ones. In the HIV-1 group two patients exhibited markedly increased GPR15 expression, with up to 46.5% of cells in the central memory subset and up to 39% of cells in the effector memory subset expressing GPR15 (Figure 1C). To exclude that environmental factors at the time point of blood drawing influenced GPR15 expression, samples from the two patients with high GPR15 expression were collected 2 month later and again analyzed for GPR15 surface levels. GPR15 expression on CD4+ from the two patient specimens was still markedly higher than GPR15 levels on cells from two uninfected controls (Figure 1D) and similar results were obtained for CD8+ T cells (Figure 1D). The viral load and age was not different between HIV-1 infected individuals expressing high and average levels of GPR15 and the reason for the increased GPR15 expression in some patients is at present unclear. Finally, we assessed whether the expression of other co-receptors, CXCR6, CCR5 and CXCR4, also was modulated in the context of HIV-1 infection. The expression of these receptors was not altered in the HIV-1 infected compared to the uninfected controls (Figure 1E). Thus, the highest expression of GPR15 in healthy individuals and HIV-1 patients is found on central memory T cells and some HIV-1 patients' exhibit markedly elevated GPR15 levels.


Toll-like receptor 3 signalling up-regulates expression of the HIV co-receptor G-protein coupled receptor 15 on human CD4+ T cells.

Kiene M, Rethi B, Jansson M, Dillon S, Lee E, Lantto R, Wilson C, Pöhlmann S, Chiodi F - PLoS ONE (2014)

GPR15 is mostly present on central memory CD4+Tcells in HIV-1 infected individuals and uninfected controls.PBMCs were isolated from whole blood by Lymphoprep gradient centrifugation and stained for CD3, CD4, CCR7, CD45RA and GPR15. (A) Cells were gated for lymphocytes, CD3+, CD4+ and CCR7+CD45RA− (CM: central memory), CCR7−CD45RA− (EM: effector memory) or CCR7+CD45RA+ (N: naïve) (A) and GPR15 expression on the subsets was analyzed via FACS (B). The GPR15 expression on CD4+ T cell subpopulations was analyzed in eight uninfected controls and eleven HIV-1 infected patients (C) as indicated in (A, B). GPR15 expression is shown as the percent of the analysed subpopulation which expresses the co-receptor (C). Blood samples taken two month later from the two high GPR15 expressing HIV-1 infected patients and two controls (shown in C) were stained for GPR15, CD4 and CD8 (D) or CD4 and other co-receptors like CXCR4, CCR5 and CXCR6 (E). The co-receptor expressions are shown as a percent of CD4+ and CD8+ T cells expressing GPR15 (D) or of CD4+ T cells expressing CXCR4, CCR5 or CXCR6 (E). Statistical analysis was done using Wilcoxon signed-rank test with GraphPad Prism.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3928197&req=5

pone-0088195-g001: GPR15 is mostly present on central memory CD4+Tcells in HIV-1 infected individuals and uninfected controls.PBMCs were isolated from whole blood by Lymphoprep gradient centrifugation and stained for CD3, CD4, CCR7, CD45RA and GPR15. (A) Cells were gated for lymphocytes, CD3+, CD4+ and CCR7+CD45RA− (CM: central memory), CCR7−CD45RA− (EM: effector memory) or CCR7+CD45RA+ (N: naïve) (A) and GPR15 expression on the subsets was analyzed via FACS (B). The GPR15 expression on CD4+ T cell subpopulations was analyzed in eight uninfected controls and eleven HIV-1 infected patients (C) as indicated in (A, B). GPR15 expression is shown as the percent of the analysed subpopulation which expresses the co-receptor (C). Blood samples taken two month later from the two high GPR15 expressing HIV-1 infected patients and two controls (shown in C) were stained for GPR15, CD4 and CD8 (D) or CD4 and other co-receptors like CXCR4, CCR5 and CXCR6 (E). The co-receptor expressions are shown as a percent of CD4+ and CD8+ T cells expressing GPR15 (D) or of CD4+ T cells expressing CXCR4, CCR5 or CXCR6 (E). Statistical analysis was done using Wilcoxon signed-rank test with GraphPad Prism.
Mentions: We have previously reported that GPR15 is expressed on central memory and, to a lesser extent, on effector memory T cells while expression of this receptor on naïve T cells is absent [23]. To investigate whether GPR15 expression on these T cell subsets is altered in the context of HIV-1 infection, we analyzed surface expression of GPR15 on CCR7+CD45RA− central memory, CCR7−CD45RA− effector memory and CCR7+CD45RA+ naïve CD4+ T cells (Figures 1A and 1B) from healthy donors and HIV-1 infected individuals. In line with our previous results [23], GPR15 was expressed to a significantly higher level on central memory (7±2.4%) compared to effector memory (3.7±2.2%; p = 0.026) and naïve CD4+ T cells (no detectable expression) (p = 0.016) in non-infected controls. A similar expression pattern was observed for HIV-1 infected individuals (ART treated and non-treated individuals) (Figure 1C), with no significant differences when comparing the levels to the non-infected controls. Although a limited number of specimens obtained from ART naïve patients was used in the study, we could not find a significant difference in GPR15 expression whencomparing ART treated HIV-1 infected individuals to the non-treated ones. In the HIV-1 group two patients exhibited markedly increased GPR15 expression, with up to 46.5% of cells in the central memory subset and up to 39% of cells in the effector memory subset expressing GPR15 (Figure 1C). To exclude that environmental factors at the time point of blood drawing influenced GPR15 expression, samples from the two patients with high GPR15 expression were collected 2 month later and again analyzed for GPR15 surface levels. GPR15 expression on CD4+ from the two patient specimens was still markedly higher than GPR15 levels on cells from two uninfected controls (Figure 1D) and similar results were obtained for CD8+ T cells (Figure 1D). The viral load and age was not different between HIV-1 infected individuals expressing high and average levels of GPR15 and the reason for the increased GPR15 expression in some patients is at present unclear. Finally, we assessed whether the expression of other co-receptors, CXCR6, CCR5 and CXCR4, also was modulated in the context of HIV-1 infection. The expression of these receptors was not altered in the HIV-1 infected compared to the uninfected controls (Figure 1E). Thus, the highest expression of GPR15 in healthy individuals and HIV-1 patients is found on central memory T cells and some HIV-1 patients' exhibit markedly elevated GPR15 levels.

Bottom Line: Here, we show that GPR15 expression in CD4(+) T cells is markedly up-regulated in some HIV-1 infected individuals compared to the rest of the infected patients and to healthy controls.Up-regulation of GPR15 expression on CD4(+) T cells was induced by activation of Toll-like receptor 3 signalling via TIR-domain-containing adapter-inducing interferon-β (TRIF) and was more prominent on gut-homing compared to lymph node-homing CD4(+) T cells.These results suggest that infection-induced up-regulation of GPR15 expression could increase susceptibility of CD4(+) T cells to HIV infection and target cell availability in the gut in some infected individuals.

View Article: PubMed Central - PubMed

Affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany ; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Background: Many HIV-2 and SIV isolates, as well as some HIV-1 strains, can use the orphan 7-transmembrane receptor GPR15 as co-receptor for efficient entry into host cells. GPR15 is expressed on central memory and effector memory CD4(+) T cells in healthy individuals and a subset of these cells is susceptible to HIV-1 and SIV infection. However, it has not been determined whether GPR15 expression is altered in the context of HIV-1 infection.

Results: Here, we show that GPR15 expression in CD4(+) T cells is markedly up-regulated in some HIV-1 infected individuals compared to the rest of the infected patients and to healthy controls. Infection of the PM1 T cell line with primary HIV-1 isolates was found to up-regulate GPR15 expression on the infected cells, indicating that viral components can induce GPR15 expression. Up-regulation of GPR15 expression on CD4(+) T cells was induced by activation of Toll-like receptor 3 signalling via TIR-domain-containing adapter-inducing interferon-β (TRIF) and was more prominent on gut-homing compared to lymph node-homing CD4(+) T cells.

Conclusion: These results suggest that infection-induced up-regulation of GPR15 expression could increase susceptibility of CD4(+) T cells to HIV infection and target cell availability in the gut in some infected individuals.

Show MeSH
Related in: MedlinePlus