Title |
Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection
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Published in |
Clinical Infectious Diseases, March 2017
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DOI | 10.1093/cid/cix201 |
Pubmed ID | |
Authors |
Line Vibholm, Mariane H. Schleimann, Jesper F. Højen, Thomas Benfield, Rasmus Offersen, Katrine Rasmussen, Rikke Olesen, Anders Dige, Jørgen Agnholt, Judith Grau, Maria Buzon, Burghardt Wittig, Mathias Lichterfeld, Andreas Munk Petersen, Xutao Deng, Mohamed Abdel-Mohsen, Satish K. Pillai, Sofie Rutsaert, Wim Trypsteen, Ward De Spiegelaere, Linos Vandekerchove, Lars Østergaard, Thomas A. Rasmussen, Paul W. Denton, Martin Tolstrup, Ole S. Søgaard |
Abstract |
Treatment with latency reversing agents (LRA) enhances HIV-1 transcription in vivo but only leads to 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. We conducted a single-arm, open-label study, where 15 virologically suppressed HIV-1 infected individuals on antiretroviral therapy received 60 mg MGN1703 s.c. twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, 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. 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- 2 levels (p<0.0001). Consistently, transcription of interferon-stimulated genes (e.g. OAS1, ISG15, Mx1; each were p<0.0001) 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) during treatment. 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. ClinicalTrials.gov: NCT02443935. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 22% |
United States | 2 | 22% |
Belgium | 2 | 22% |
Canada | 1 | 11% |
Unknown | 2 | 22% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 4 | 44% |
Members of the public | 3 | 33% |
Science communicators (journalists, bloggers, editors) | 1 | 11% |
Practitioners (doctors, other healthcare professionals) | 1 | 11% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 129 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 26 | 20% |
Student > Ph. D. Student | 21 | 16% |
Student > Bachelor | 14 | 11% |
Student > Master | 11 | 9% |
Other | 8 | 6% |
Other | 18 | 14% |
Unknown | 31 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 26 | 20% |
Medicine and Dentistry | 24 | 19% |
Agricultural and Biological Sciences | 18 | 14% |
Immunology and Microbiology | 14 | 11% |
Chemistry | 2 | 2% |
Other | 5 | 4% |
Unknown | 40 | 31% |