Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection
Research output: Contribution to journal › Journal article › Research › peer-review
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 language | English |
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Journal | Clinical Infectious Diseases |
Volume | 64 |
Issue number | 12 |
Pages (from-to) | 1686-1695 |
ISSN | 1058-4838 |
DOIs | |
Publication status | Published - 15 Jun 2017 |
- 2',5'-Oligoadenylate Synthetase/genetics, Antiretroviral Therapy, Highly Active, CD8-Positive T-Lymphocytes/drug effects, Cytokines/genetics, DNA/administration & dosage, Dendritic Cells/drug effects, Female, HIV Infections/drug therapy, HIV-1/drug effects, Humans, Immunity, Innate/drug effects, Interferon-alpha/blood, Killer Cells, Natural/drug effects, Lymphocyte Activation/drug effects, Male, Middle Aged, Myxovirus Resistance Proteins/genetics, RNA, Viral/adverse effects, Toll-Like Receptor 9/agonists, Ubiquitins/genetics, Viremia/blood, Virus Latency/drug effects
Research areas
ID: 193664839