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Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection

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Harvard

Vibholm, L, Schleimann, MH, Højen, JF, Benfield, T, Offersen, R, Rasmussen, KL, Olesen, R, Dige, A, Agnholt, J, Grau, J, Buzon, M, Wittig, B, Lichterfeld, M, Petersen, AM, Deng, X, Abdel-Mohsen, M, Pillai, SK, Rutsaert, S, Trypsteen, W, De Spiegelaere, W, Vandekerchove, L, Østergaard, L, Rasmussen, TA, Denton, PW, Tolstrup, M & Søgaard, OS 2017, 'Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection', Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, bind 64, nr. 12, s. 1686-1695. https://doi.org/10.1093/cid/cix201

APA

Vibholm, L., Schleimann, M. H., Højen, J. F., Benfield, T., Offersen, R., Rasmussen, K. L., Olesen, R., Dige, A., Agnholt, J., Grau, J., Buzon, M., Wittig, B., Lichterfeld, M., Petersen, A. M., Deng, X., Abdel-Mohsen, M., Pillai, S. K., Rutsaert, S., Trypsteen, W., ... Søgaard, O. S. (2017). Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 64(12), 1686-1695. https://doi.org/10.1093/cid/cix201

CBE

Vibholm L, Schleimann MH, Højen JF, Benfield T, Offersen R, Rasmussen KL, Olesen R, Dige A, Agnholt J, Grau J, Buzon M, Wittig B, Lichterfeld M, Petersen AM, Deng X, Abdel-Mohsen M, Pillai SK, Rutsaert S, Trypsteen W, De Spiegelaere W, Vandekerchove L, Østergaard L, Rasmussen TA, Denton PW, Tolstrup M, Søgaard OS. 2017. Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 64(12):1686-1695. https://doi.org/10.1093/cid/cix201

MLA

Vancouver

Author

Vibholm, Line ; Schleimann, Mariane H ; Højen, Jesper F ; Benfield, Thomas ; Offersen, Rasmus ; Rasmussen, Katrine Laura ; Olesen, Rikke ; Dige, Anders ; Agnholt, Jørgen ; Grau, Judith ; Buzon, Maria ; Wittig, Burghardt ; Lichterfeld, Mathias ; Petersen, Andreas Munk ; Deng, Xutao ; Abdel-Mohsen, Mohammed ; Pillai, Satish K ; Rutsaert, Sofie ; Trypsteen, Wim ; De Spiegelaere, Ward ; Vandekerchove, Linos ; Østergaard, Lars ; Rasmussen, Thomas A ; Denton, Paul W ; Tolstrup, Martin ; Søgaard, Ole S. / Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection. I: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 ; Bind 64, Nr. 12. s. 1686-1695.

Bibtex

@article{55d48bbbc77a4b559b1e3ba6fe327ffe,
title = "Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection",
abstract = "Background: Treatment with latency reversing agents (LRA) enhances HIV-1 transcription in vivo but only leads to modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule - a novel toll-like receptor 9 (TLR9) agonist, MGN1703 - could function as an enhancer of innate immunity and an LRA in vivo.Methods: We conducted a single-arm, open-label study, where 15 virologically suppressed HIV-1 infected individuals on antiretroviral therapy received 60 mg MGN1703 s.c. twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, NK -and T cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration.Results: In accordance with the cell-type specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon- 2 levels (p<0.0001). Consistently, transcription of interferon-stimulated genes (e.g. OAS1, ISG15, Mx1; each were p<0.0001) were upregulated in CD4+ T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8+ T cells increased significantly during MGN1703 dosing suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from <20 copies/mL to >1500 copies/mL (range 21-1571) during treatment.Conclusions: TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy. ClinicalTrials.gov: NCT02443935.",
keywords = "Journal Article",
author = "Line Vibholm and Schleimann, {Mariane H} and H{\o}jen, {Jesper F} and Thomas Benfield and Rasmus Offersen and Rasmussen, {Katrine Laura} and Rikke Olesen and Anders Dige and J{\o}rgen Agnholt and Judith Grau and Maria Buzon and Burghardt Wittig and Mathias Lichterfeld and Petersen, {Andreas Munk} and Xutao Deng and Mohammed Abdel-Mohsen and Pillai, {Satish K} and Sofie Rutsaert and Wim Trypsteen and {De Spiegelaere}, Ward and Linos Vandekerchove and Lars {\O}stergaard and Rasmussen, {Thomas A} and Denton, {Paul W} and Martin Tolstrup and S{\o}gaard, {Ole S}",
year = "2017",
month = jun,
day = "1",
doi = "10.1093/cid/cix201",
language = "English",
volume = "64",
pages = "1686--1695",
journal = "Clinical Infectious Diseases",
issn = "1058-4838",
publisher = "University of Chicago Press",
number = "12",

}

RIS

TY - JOUR

T1 - Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection

AU - Vibholm, Line

AU - Schleimann, Mariane H

AU - Højen, Jesper F

AU - Benfield, Thomas

AU - Offersen, Rasmus

AU - Rasmussen, Katrine Laura

AU - Olesen, Rikke

AU - Dige, Anders

AU - Agnholt, Jørgen

AU - Grau, Judith

AU - Buzon, Maria

AU - Wittig, Burghardt

AU - Lichterfeld, Mathias

AU - Petersen, Andreas Munk

AU - Deng, Xutao

AU - Abdel-Mohsen, Mohammed

AU - Pillai, Satish K

AU - Rutsaert, Sofie

AU - Trypsteen, Wim

AU - De Spiegelaere, Ward

AU - Vandekerchove, Linos

AU - Østergaard, Lars

AU - Rasmussen, Thomas A

AU - Denton, Paul W

AU - Tolstrup, Martin

AU - Søgaard, Ole S

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background: Treatment with latency reversing agents (LRA) enhances HIV-1 transcription in vivo but only leads to modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule - a novel toll-like receptor 9 (TLR9) agonist, MGN1703 - could function as an enhancer of innate immunity and an LRA in vivo.Methods: We conducted a single-arm, open-label study, where 15 virologically suppressed HIV-1 infected individuals on antiretroviral therapy received 60 mg MGN1703 s.c. twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, NK -and T cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration.Results: In accordance with the cell-type specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon- 2 levels (p<0.0001). Consistently, transcription of interferon-stimulated genes (e.g. OAS1, ISG15, Mx1; each were p<0.0001) were upregulated in CD4+ T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8+ T cells increased significantly during MGN1703 dosing suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from <20 copies/mL to >1500 copies/mL (range 21-1571) during treatment.Conclusions: TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy. ClinicalTrials.gov: NCT02443935.

AB - Background: Treatment with latency reversing agents (LRA) enhances HIV-1 transcription in vivo but only leads to modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule - a novel toll-like receptor 9 (TLR9) agonist, MGN1703 - could function as an enhancer of innate immunity and an LRA in vivo.Methods: We conducted a single-arm, open-label study, where 15 virologically suppressed HIV-1 infected individuals on antiretroviral therapy received 60 mg MGN1703 s.c. twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, NK -and T cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration.Results: In accordance with the cell-type specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon- 2 levels (p<0.0001). Consistently, transcription of interferon-stimulated genes (e.g. OAS1, ISG15, Mx1; each were p<0.0001) were upregulated in CD4+ T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8+ T cells increased significantly during MGN1703 dosing suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from <20 copies/mL to >1500 copies/mL (range 21-1571) during treatment.Conclusions: TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy. ClinicalTrials.gov: NCT02443935.

KW - Journal Article

U2 - 10.1093/cid/cix201

DO - 10.1093/cid/cix201

M3 - Journal article

C2 - 28329286

VL - 64

SP - 1686

EP - 1695

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

IS - 12

ER -

ID: 50133083