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Plasmacytoid dendritic cells suppress HIV-1 replication but contribute to HIV-1 induced immunopathogenesis in humanized mice.

Li G, Cheng M, Nunoya J, Cheng L, Guo H, Yu H, Liu YJ, Su L, Zhang L - PLoS Pathog. (2014)

Bottom Line: The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells.We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis.These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

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Depletion of pDC during chronic infection reduces HIV-1 induced immunopathogenesis.Humanized mice were infected HIV-JRCSF and were treated weekly with 15B or control at 11 weeks post-infection and terminated at 21 weeks post-infection (mock, n = 6; JR-CSF+control, n = 9; JR-CSF+15B, n = 9). (A–C) Summarized data show relative numbers in PBL and SP of (A) CD4 T cells (CD3+CD8−), (B) CD8 T cells (CD3+CD4−CD8+), and (C) human CD45+ leukocytes. (D) Immunohistochemistry staining for human CD45+ cells in spleens of mock or HIV-1 infected mice. (E) FACS plots of cell death in human CD4+ T cells, CD8+ T cells and huCD45+ leukocytes from spleens. (F) Summary data show percentages of cell death in CD4+ T cells, CD8+ T cells and huCD45+ leukocytes. Bars in dot graphs indicate median value. * and ** indicate p<0.05 and p<0.01, respectively.
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ppat-1004291-g007: Depletion of pDC during chronic infection reduces HIV-1 induced immunopathogenesis.Humanized mice were infected HIV-JRCSF and were treated weekly with 15B or control at 11 weeks post-infection and terminated at 21 weeks post-infection (mock, n = 6; JR-CSF+control, n = 9; JR-CSF+15B, n = 9). (A–C) Summarized data show relative numbers in PBL and SP of (A) CD4 T cells (CD3+CD8−), (B) CD8 T cells (CD3+CD4−CD8+), and (C) human CD45+ leukocytes. (D) Immunohistochemistry staining for human CD45+ cells in spleens of mock or HIV-1 infected mice. (E) FACS plots of cell death in human CD4+ T cells, CD8+ T cells and huCD45+ leukocytes from spleens. (F) Summary data show percentages of cell death in CD4+ T cells, CD8+ T cells and huCD45+ leukocytes. Bars in dot graphs indicate median value. * and ** indicate p<0.05 and p<0.01, respectively.

Mentions: In spite of the persistently higher viremia during 10 weeks of pDC depletion treatment, human CD4+ T cell numbers increased significantly in the spleen, comparing to the control group (Figure 7A, p<0.05). In addition, human CD8 T cells and CD45+ leukocyte numbers in spleens were also increased (Figure 7B&C, p<0.01). Interestingly, the relative depletion of human CD4, CD8 T cells and CD45 leukocytes was the same in the blood (Figure 7A–C). The increase of human CD45+ cells in the spleen was also confirmed by immunohistochemistry staining of spleen sections (Figure 7D). Accordingly, pDC depletion significantly reduced the percentage of dying cells in T cells and total human CD45+ cells in the spleen and other lymphoid organs (Figure 7E&F and data not shown). Therefore, persistent activation of pDC in lymphoid organs during HIV-1 chronic infection, although still producing IFN-I to suppress HIV-1 replication, contributes significantly to HIV-1 induced depletion of human leukocytes including human CD4 T cells.


Plasmacytoid dendritic cells suppress HIV-1 replication but contribute to HIV-1 induced immunopathogenesis in humanized mice.

Li G, Cheng M, Nunoya J, Cheng L, Guo H, Yu H, Liu YJ, Su L, Zhang L - PLoS Pathog. (2014)

Depletion of pDC during chronic infection reduces HIV-1 induced immunopathogenesis.Humanized mice were infected HIV-JRCSF and were treated weekly with 15B or control at 11 weeks post-infection and terminated at 21 weeks post-infection (mock, n = 6; JR-CSF+control, n = 9; JR-CSF+15B, n = 9). (A–C) Summarized data show relative numbers in PBL and SP of (A) CD4 T cells (CD3+CD8−), (B) CD8 T cells (CD3+CD4−CD8+), and (C) human CD45+ leukocytes. (D) Immunohistochemistry staining for human CD45+ cells in spleens of mock or HIV-1 infected mice. (E) FACS plots of cell death in human CD4+ T cells, CD8+ T cells and huCD45+ leukocytes from spleens. (F) Summary data show percentages of cell death in CD4+ T cells, CD8+ T cells and huCD45+ leukocytes. Bars in dot graphs indicate median value. * and ** indicate p<0.05 and p<0.01, respectively.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4117636&req=5

ppat-1004291-g007: Depletion of pDC during chronic infection reduces HIV-1 induced immunopathogenesis.Humanized mice were infected HIV-JRCSF and were treated weekly with 15B or control at 11 weeks post-infection and terminated at 21 weeks post-infection (mock, n = 6; JR-CSF+control, n = 9; JR-CSF+15B, n = 9). (A–C) Summarized data show relative numbers in PBL and SP of (A) CD4 T cells (CD3+CD8−), (B) CD8 T cells (CD3+CD4−CD8+), and (C) human CD45+ leukocytes. (D) Immunohistochemistry staining for human CD45+ cells in spleens of mock or HIV-1 infected mice. (E) FACS plots of cell death in human CD4+ T cells, CD8+ T cells and huCD45+ leukocytes from spleens. (F) Summary data show percentages of cell death in CD4+ T cells, CD8+ T cells and huCD45+ leukocytes. Bars in dot graphs indicate median value. * and ** indicate p<0.05 and p<0.01, respectively.
Mentions: In spite of the persistently higher viremia during 10 weeks of pDC depletion treatment, human CD4+ T cell numbers increased significantly in the spleen, comparing to the control group (Figure 7A, p<0.05). In addition, human CD8 T cells and CD45+ leukocyte numbers in spleens were also increased (Figure 7B&C, p<0.01). Interestingly, the relative depletion of human CD4, CD8 T cells and CD45 leukocytes was the same in the blood (Figure 7A–C). The increase of human CD45+ cells in the spleen was also confirmed by immunohistochemistry staining of spleen sections (Figure 7D). Accordingly, pDC depletion significantly reduced the percentage of dying cells in T cells and total human CD45+ cells in the spleen and other lymphoid organs (Figure 7E&F and data not shown). Therefore, persistent activation of pDC in lymphoid organs during HIV-1 chronic infection, although still producing IFN-I to suppress HIV-1 replication, contributes significantly to HIV-1 induced depletion of human leukocytes including human CD4 T cells.

Bottom Line: The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells.We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis.These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

Show MeSH
Related in: MedlinePlus