A novel Toll-like receptor 9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1-infected autologous CD4+ T cells

Rasmus Offersen, Sara Konstantin Nissen, Thomas A. Rasmussen, Lars Østergaard, Paul W. Denton, Ole Schmeltz Søgaard, Martin Tolstrup

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR agonists have a potential role in the context of a "shock-and-kill" approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that a novel TLR9 agonist, MGN1703, may indeed perform both functions in an HIV-1 eradication trial. Peripheral blood mononuclear cells (PBMCs) from aviremic HIV-1-infected donors on antiretroviral therapy (ART) that were incubated with MGN1703 ex vivo exhibited increased secretion of interferon alpha (IFN-α) (P=0.005) and CXCL10 (P= 0.0005) in culture supernatants. Within the incubated PBMC pool, there were higher proportions of CD69-positive CD56dim CD16+ NK cells (P=0.001) as well as higher proportions of CD107a-positive (P=0.002) and IFN-γ-producing (P=0.038) NK cells. Incubation with MGN1703 also increased the proportions of CD69-expressing CD4+ and CD8+ T cells. Furthermore, CD4+ T cells within the pool of MGN1703-incubated PBMCs showed enhanced levels of unspliced HIV-1 RNA (P=0.036). Importantly, MGN1703 increased the capacity of NK cells to inhibit virus spread within a culture of autologous CD4+ T cells assessed by using an HIV-1 p24 enzyme-linked immunosorbent assay (ELISA) (P=0.03). In conclusion, we show that MGN1703 induced strong antiviral innate immune responses, enhanced HIV-1 transcription, and boosted NK cell-mediated suppression of HIV-1 infection in autologous CD4+ T cells. These findings support clinical testing of MGN1703 in HIV-1 eradication trials.

Original languageEnglish (US)
Pages (from-to)4441-4453
Number of pages13
JournalJournal of virology
Volume90
Issue number9
DOIs
StatePublished - May 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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