Dataset Information

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.

SUBMITTER: Vibholm L

PROVIDER: S-EPMC5849129 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Vibholm Line L Schleimann Mariane H MH Højen Jesper F JF Benfield Thomas T Offersen Rasmus R Rasmussen Katrine K Olesen Rikke R Dige Anders A Agnholt Jørgen J Agnholt Jørgen J Grau Judith J Buzon Maria M Wittig Burghardt B Lichterfeld Mathias M Petersen Andreas Munk AM Deng Xutao X Abdel-Mohsen Mohamed M Pillai Satish K SK Rutsaert Sofie S Trypsteen Wim W De Spiegelaere Ward W Vandekerchove Linos L Østergaard Lars L Rasmussen Thomas A TA Denton Paul W PW Tolstrup Martin M Søgaard Ole S OS

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20170601 12

<h4>Background.</h4>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.<h4>Methods.</h4>We conducted a single-arm, open-la ...[more]

PMID: 28329286

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Dataset Information

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

Background.

Methods.

Results.

Conclusions.

Clinical trials registration.

Publications

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

Similar Datasets

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