title: 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.
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 CD56(dim)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.
  
  
  OBJECTIVE
  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 individuals on suppressive antiretroviral therapy. The significantly improved safety and tolerability profiles of MGN1703 versus TLR9 agonists of the CpG-oligodeoxynucleotide (CpG-ODN) family are due to its novel "dumbbell-shape" structure made of covalently closed, natural DNA. In our study, we found that incubation of peripheral blood mononuclear cells with MGN1703 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.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark rasmus.offersen@gmail.com marttols@rm.dk.|Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Offersen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.|Institute of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Sara Konstantin
authors.initials: SK
authors.lastname: Nissen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.|Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.|Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.|Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Ole Schmeltz
authors.initials: OS
authors.lastname: Søgaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark rasmus.offersen@gmail.com marttols@rm.dk.|Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
mesh_terms: D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D016022:Case-Control Studies; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007694:Killer Cells, Natural / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic; D019562:Viral Load; D017735:Virus Latency
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; C000597235:MGN1703; C112260:NCR1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055627:Natural Cytotoxicity Triggering Receptor 1; D012367:RNA, Viral; D051217:Toll-Like Receptor 9; D004247:DNA