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

N1 - © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

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

VL - 64

SP - 1686

EP - 1695

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

IS - 12

ER -