Lars Jørgen Østergaard

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

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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. PBMCs from aviremic HIV-1 infected donors on ART, that were incubated with MGN1703 ex vivo, exhibited increased secretion of 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 CD56(dim)CD16(+) NK cells (p=0.001) as well as higher proportions of CD107a positive (p=0.002) and IFN-γ producing NK cells (p=0.038). MGN1703 incubation 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 viral spreading within a culture of autologous CD4+ T cells assessed using HIV-1 p24 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.

IMPORTANCE: We demonstrate, that MGN1703 (a TLR9 agonist currently undergoing phase 3 clinical testing for the treatment of metastatic colorectal cancer) induces potent antiviral responses in immune effector cells from HIV-1-infected on suppressive antiretroviral therapy. The significant improved safety and tolerability profile of MGN1703 versus TLR9 agonists of the CpG-ODN family is due to its novel "dumbbell shape" structure made of covalently-closed, natural DNA. In our study, we found that MGN1703 incubation of peripheral blood mononuclear cells results in natural killer cell activation and increased natural killer cell function, which significantly inhibited the spread of HIV in a culture of autologous CD4+ T cells. Furthermore, we discovered that MGN1703-mediated activation can enhance HIV-1 transcription in CD4+ T cells suggesting that this molecule may serve a dual purpose in HIV-1 eradication therapy: enhanced immune function and latency reversal. These findings provide a strong preclinical basis for the inclusion of MGN1703 in an HIV eradication clinical trial.

Original languageEnglish
JournalJournal of Virology
ISSN0022-538X
DOIs
Publication statusPublished - 17 Feb 2016

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