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, Katrine Rasmussen, Rikke Olesen, 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 SpiegelaereLinos Vandekerchove, Lars Østergaard, Thomas A. Rasmussen, Paul W. Denton, Martin Tolstrup, Ole S. Søgaard

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1686-1695
Number of pages10
JournalClinical Infectious Diseases
Volume64
Issue number12
DOIs
StatePublished - Jun 15 2017

Keywords

  • NK cell activation.
  • TLR9 agonist
  • immune therapeutic treatment
  • latency reversal
  • latent HIV-1 infection

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Short-course toll-like receptor 9 agonist treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection'. Together they form a unique fingerprint.

Cite this