Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

Clin Infect Dis. 2017 Jun 15;64(12):1686-1695. doi: 10.1093/cid/cix201.


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.

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

Publication types

  • Clinical Trial

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics
  • Antiretroviral Therapy, Highly Active
  • CD8-Positive T-Lymphocytes / drug effects
  • Cytokines / genetics
  • DNA / administration & dosage
  • DNA / therapeutic use*
  • Dendritic Cells / drug effects
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • Humans
  • Immunity, Innate / drug effects*
  • Immunity, Innate / genetics
  • Interferon-alpha / blood
  • Interferon-alpha / drug effects
  • Killer Cells, Natural / drug effects
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Myxovirus Resistance Proteins / genetics
  • RNA, Viral / adverse effects
  • RNA, Viral / blood
  • Toll-Like Receptor 9 / agonists*
  • Toll-Like Receptor 9 / genetics
  • Ubiquitins / genetics
  • Viremia / blood
  • Viremia / drug therapy*
  • Virus Latency / drug effects


  • Cytokines
  • Interferon-alpha
  • MGN1703
  • MX1 protein, human
  • Myxovirus Resistance Proteins
  • RNA, Viral
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Ubiquitins
  • ISG15 protein, human
  • DNA
  • OAS1 protein, human
  • 2',5'-Oligoadenylate Synthetase

Associated data