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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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Pre-infection depletion of pDC abolishes IFN-I induction during acute HIV-1 infection in humanized mice.(A) Summarized data of pDC percentages in total human leukocytes (CD45+) from humanized mice are shown mice. Mice were treated with either 15B or isotype control (iso) antibody. After pDC depletion, mice were infected with HIV-R3A and terminated on 8 days post infection (dpi) for analysis. Mock infected mice, n = 6; isotype+R3A infected mice, n = 9; 15B+R3A infected mice, n = 12. (B) Plasma levels of IFN-α2 from mock, HIV-1 infected and 15B or isotype mAb treated mice were quantified by Luminex assays. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. (C) The mRNA expression of major type I IFN genes in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. (D) ISGs (Mx1 and TRIM22) expression in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. Mice were analyzed at 8 days post infection. Error bars in graphs indicate median value. Error bars indicate standard deviations (SD). * and ** indicate p<0.05 and p<0.01, respectively.
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ppat-1004291-g003: Pre-infection depletion of pDC abolishes IFN-I induction during acute HIV-1 infection in humanized mice.(A) Summarized data of pDC percentages in total human leukocytes (CD45+) from humanized mice are shown mice. Mice were treated with either 15B or isotype control (iso) antibody. After pDC depletion, mice were infected with HIV-R3A and terminated on 8 days post infection (dpi) for analysis. Mock infected mice, n = 6; isotype+R3A infected mice, n = 9; 15B+R3A infected mice, n = 12. (B) Plasma levels of IFN-α2 from mock, HIV-1 infected and 15B or isotype mAb treated mice were quantified by Luminex assays. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. (C) The mRNA expression of major type I IFN genes in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. (D) ISGs (Mx1 and TRIM22) expression in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. Mice were analyzed at 8 days post infection. Error bars in graphs indicate median value. Error bars indicate standard deviations (SD). * and ** indicate p<0.05 and p<0.01, respectively.

Mentions: To test the role of pDC in early acute HIV-1 infection, we injected 15B and isotype control antibody into humanized mice on -5, -3 and -1 days before infection, and then infected them with HIV-R3A (a highly pathogenic dual-tropic HIV-1 strain, [44], [45]) on day 0. The infected mice were treated with 15B or control antibody two more times on 3 and 6 days post-infection (dpi). We found that pDC remained depleted in blood and lymphoid organs of the infected mice (Figure 3A), when terminated on 8 dpi. Interestingly, the induction of plasma IFN-I was completely blocked by pDC depletion in HIV-1 infected mice (Figure 3B). The suppressed expression of different subtypes of human IFN-I was also confirmed at RNA level by real time PCR (Figure 3C). In addition, the up-regulation of ISGs such as Mx1 and TRIM22 was also blocked (Figure 3D and data not shown). We confirmed similar blocking of IFN-I induction by pDC-depletion prior to infection with the CCR5-tropic JRCSF HIV-1 strain (data not shown). These data demonstrate that pDC are the critical IFN-I producing cells during early HIV-1 infection in humanized mice in vivo.


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)

Pre-infection depletion of pDC abolishes IFN-I induction during acute HIV-1 infection in humanized mice.(A) Summarized data of pDC percentages in total human leukocytes (CD45+) from humanized mice are shown mice. Mice were treated with either 15B or isotype control (iso) antibody. After pDC depletion, mice were infected with HIV-R3A and terminated on 8 days post infection (dpi) for analysis. Mock infected mice, n = 6; isotype+R3A infected mice, n = 9; 15B+R3A infected mice, n = 12. (B) Plasma levels of IFN-α2 from mock, HIV-1 infected and 15B or isotype mAb treated mice were quantified by Luminex assays. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. (C) The mRNA expression of major type I IFN genes in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. (D) ISGs (Mx1 and TRIM22) expression in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. Mice were analyzed at 8 days post infection. Error bars in graphs indicate median value. Error bars indicate standard deviations (SD). * and ** indicate p<0.05 and p<0.01, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4117636&req=5

ppat-1004291-g003: Pre-infection depletion of pDC abolishes IFN-I induction during acute HIV-1 infection in humanized mice.(A) Summarized data of pDC percentages in total human leukocytes (CD45+) from humanized mice are shown mice. Mice were treated with either 15B or isotype control (iso) antibody. After pDC depletion, mice were infected with HIV-R3A and terminated on 8 days post infection (dpi) for analysis. Mock infected mice, n = 6; isotype+R3A infected mice, n = 9; 15B+R3A infected mice, n = 12. (B) Plasma levels of IFN-α2 from mock, HIV-1 infected and 15B or isotype mAb treated mice were quantified by Luminex assays. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. (C) The mRNA expression of major type I IFN genes in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. (D) ISGs (Mx1 and TRIM22) expression in purified human cells (CD45+) from mouse spleens was measured by real-time PCR. Mock, n = 3; isotype+R3A, n = 5; 15B+R3A, n = 5. Mice were analyzed at 8 days post infection. Error bars in graphs indicate median value. Error bars indicate standard deviations (SD). * and ** indicate p<0.05 and p<0.01, respectively.
Mentions: To test the role of pDC in early acute HIV-1 infection, we injected 15B and isotype control antibody into humanized mice on -5, -3 and -1 days before infection, and then infected them with HIV-R3A (a highly pathogenic dual-tropic HIV-1 strain, [44], [45]) on day 0. The infected mice were treated with 15B or control antibody two more times on 3 and 6 days post-infection (dpi). We found that pDC remained depleted in blood and lymphoid organs of the infected mice (Figure 3A), when terminated on 8 dpi. Interestingly, the induction of plasma IFN-I was completely blocked by pDC depletion in HIV-1 infected mice (Figure 3B). The suppressed expression of different subtypes of human IFN-I was also confirmed at RNA level by real time PCR (Figure 3C). In addition, the up-regulation of ISGs such as Mx1 and TRIM22 was also blocked (Figure 3D and data not shown). We confirmed similar blocking of IFN-I induction by pDC-depletion prior to infection with the CCR5-tropic JRCSF HIV-1 strain (data not shown). These data demonstrate that pDC are the critical IFN-I producing cells during early HIV-1 infection in humanized mice in vivo.

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