Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

Line Vibholm; Mariane H Schleimann; Jesper F Højen; Thomas Benfield; Rasmus Offersen; Anders Dige; Jørgen Agnholt; Judith Grau; Maria Buzon; Burghardt Wittig; Mathias Lichterfeld; Andreas Munk Petersen; Xutao Deng; Mohamed Abdel-Mohsen; Satish K Pillai; Sofie Rutsaert; Wim Trypsteen; Ward De Spiegelaere; Linos Vandekerchove; Lars Østergaard; Paul W Denton; Martin Tolstrup; Ole S Søgaard

doi:10.1093/cid/cix201

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

Line Vibholm, Mariane H Schleimann, Jesper F Højen, Thomas Benfield, Rasmus Offersen, Anders Dige, Jørgen Agnholt, Judith Grau, Maria Buzon, Burghardt Wittig, Mathias Lichterfeld, Andreas Munk Petersen, Xutao Deng, Mohamed Abdel-Mohsen, Satish K Pillai, Sofie Rutsaert, Wim Trypsteen, Ward De Spiegelaere, Linos Vandekerchove, Lars ØstergaardPaul W Denton, Martin Tolstrup, Ole S Søgaard

Institut for Klinisk Medicin

63 Citationer (Scopus)

Abstract

Background.: Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only 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 in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (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-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .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 copies/mL) 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.

Clinical Trials Registration.: NCT02443935.

Originalsprog	Engelsk
Tidsskrift	Clinical Infectious Diseases
Vol/bind	64
Udgave nummer	12
Sider (fra-til)	1686-1695
ISSN	1058-4838
DOI	https://doi.org/10.1093/cid/cix201
Status	Udgivet - 15 jun. 2017

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Vibholm, L., Schleimann, M. H., Højen, J. F., Benfield, T., Offersen, 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., De Spiegelaere, W., Vandekerchove, L., ... Søgaard, O. S. (2017). Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection. Clinical Infectious Diseases, 64(12), 1686-1695. https://doi.org/10.1093/cid/cix201

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection. / Vibholm, Line; Schleimann, Mariane H; Højen, Jesper F et al.
I: Clinical Infectious Diseases, Bind 64, Nr. 12, 15.06.2017, s. 1686-1695.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Vibholm, L, Schleimann, MH, Højen, JF, Benfield, T, Offersen, 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, Denton, PW, Tolstrup, M & Søgaard, OS 2017, 'Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection', Clinical Infectious Diseases, bind 64, nr. 12, s. 1686-1695. https://doi.org/10.1093/cid/cix201

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title = "Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection",

abstract = "Background.: Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only 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 in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (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-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .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 copies/mL) 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.Clinical Trials Registration.: NCT02443935.",

keywords = "2',5'-Oligoadenylate Synthetase/genetics, Antiretroviral Therapy, Highly Active, CD8-Positive T-Lymphocytes/drug effects, Cytokines/genetics, DNA/administration & dosage, Dendritic Cells/drug effects, Female, HIV Infections/drug therapy, HIV-1/drug effects, Humans, Immunity, Innate/drug effects, Interferon-alpha/blood, Killer Cells, Natural/drug effects, Lymphocyte Activation/drug effects, Male, Middle Aged, Myxovirus Resistance Proteins/genetics, RNA, Viral/adverse effects, Toll-Like Receptor 9/agonists, Ubiquitins/genetics, Viremia/blood, Virus Latency/drug effects",

author = "Line Vibholm and Schleimann, {Mariane H} and H{\o}jen, {Jesper F} and Thomas Benfield and Rasmus Offersen 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 Mohamed Abdel-Mohsen and Pillai, {Satish K} and Sofie Rutsaert and Wim Trypsteen and {De Spiegelaere}, Ward and Linos Vandekerchove and Lars {\O}stergaard and Denton, {Paul W} and Martin Tolstrup and S{\o}gaard, {Ole S}",

year = "2017",

month = jun,

day = "15",

doi = "10.1093/cid/cix201",

language = "English",

volume = "64",

pages = "1686--1695",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "12",

}

TY - JOUR

T1 - Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

AU - Vibholm, Line

AU - Schleimann, Mariane H

AU - Højen, Jesper F

AU - Benfield, Thomas

AU - Offersen, Rasmus

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, Mohamed

AU - Pillai, Satish K

AU - Rutsaert, Sofie

AU - Trypsteen, Wim

AU - De Spiegelaere, Ward

AU - Vandekerchove, Linos

AU - Østergaard, Lars

AU - Denton, Paul W

AU - Tolstrup, Martin

AU - Søgaard, Ole S

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Background.: Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only 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 in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (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-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .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 copies/mL) 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.Clinical Trials Registration.: NCT02443935.

AB - Background.: Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only 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 in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (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-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .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 copies/mL) 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.Clinical Trials Registration.: NCT02443935.

KW - 2',5'-Oligoadenylate Synthetase/genetics

KW - Antiretroviral Therapy, Highly Active

KW - CD8-Positive T-Lymphocytes/drug effects

KW - Cytokines/genetics

KW - DNA/administration & dosage

KW - Dendritic Cells/drug effects

KW - Female

KW - HIV Infections/drug therapy

KW - HIV-1/drug effects

KW - Humans

KW - Immunity, Innate/drug effects

KW - Interferon-alpha/blood

KW - Killer Cells, Natural/drug effects

KW - Lymphocyte Activation/drug effects

KW - Male

KW - Middle Aged

KW - Myxovirus Resistance Proteins/genetics

KW - RNA, Viral/adverse effects

KW - Toll-Like Receptor 9/agonists

KW - Ubiquitins/genetics

KW - Viremia/blood

KW - Virus Latency/drug effects

U2 - 10.1093/cid/cix201

DO - 10.1093/cid/cix201

M3 - Journal article

C2 - 28329286

SN - 1058-4838

VL - 64

SP - 1686

EP - 1695

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 12

ER -

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

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