Lars Jørgen Østergaard

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

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DOI

  • Line Vibholm
  • ,
  • Mariane H Schleimann
  • Jesper F Højen
  • ,
  • Thomas Benfield, Dept. of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
  • ,
  • Rasmus Offersen
  • ,
  • Katrine Rasmussen, Dept. of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
  • ,
  • Rikke Olesen
  • Anders Dige
  • Jørgen Agnholt
  • Judith Grau, Hebron Institute of Research, Dept. of Infectious Diseases, Barcelona, Spain.
  • ,
  • Maria J Buzon, Hebron Institute of Research, Dept. of Infectious Diseases, Barcelona, Spain.
  • ,
  • Burghardt Wittig, Foundation Institute Molecular Biology and Bioinformatics, Freie Universitaet, Berlin, Germany.
  • ,
  • Mathias Lichterfeld, Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
  • ,
  • Andreas Munk Petersen, Dept. of Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
  • ,
  • Xutao Deng, Multiple Sclerosis Center, University of California San Francisco, CA, USA.
  • ,
  • Mohammed Abdel-Mohsen, Multiple Sclerosis Center, University of California San Francisco, CA, USA.
  • ,
  • Satish K Pillai, Multiple Sclerosis Center, University of California San Francisco, CA, USA.
  • ,
  • Sofie Rutsaert, Dept. of Internal Medicine, Ghent University, Ghent, Belgium.
  • ,
  • Wim Trypsteen, Dept. of Internal Medicine, Ghent University, Ghent, Belgium.
  • ,
  • Ward De Spiegelaere, Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium.
  • ,
  • Linos Vandekerchove, Dept. of Internal Medicine, Ghent University, Ghent, Belgium.
  • ,
  • Lars Jørgen Østergaard
  • Thomas A Rasmussen
  • ,
  • Paul W Denton
  • ,
  • Martin Tolstrup
  • Ole S Søgaard

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.

Original languageEnglish
JournalClinical Infectious Diseases
ISSN1058-4838
DOIs
Publication statusPublished - 15 Jun 2017

    Research areas

  • Journal Article

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