Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection.
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.
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.
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.
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.
NCT02443935.
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Line
L
Vibholm
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Mariane H
MH
Schleimann
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Jesper F
JF
Højen
Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, and.
Thomas
T
Benfield
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Rasmus
R
Offersen
Department of Infectious Diseases, Aarhus University Hospital.
Katrine
K
Rasmussen
Department of Infectious Diseases, Aarhus University Hospital.
Rikke
R
Olesen
Institute of Clinical Medicine, Aarhus University.|Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark.
Anders
A
Dige
Institute of Clinical Medicine, Aarhus University.|Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark.
Jørgen
J
Agnholt
Hebron Institute of Research, Department of Infectious Diseases, Barcelona, Spain.
Judith
J
Grau
Hebron Institute of Research, Department of Infectious Diseases, Barcelona, Spain.
Maria
M
Buzon
Foundation Institute Molecular Biology and Bioinformatics, Freie Universitaet, Berlin, Germany.
Burghardt
B
Wittig
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston; Departments of.
Mathias
M
Lichterfeld
Gastroenterology and.|Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
Andreas Munk
AM
Petersen
Blood Systems Research Institute, San Francisco, California, and.|University of California, San Francisco.
Xutao
X
Deng
Blood Systems Research Institute, San Francisco, California, and.|University of California, San Francisco.|The Wistar Institute, Philadelphia, Pennsylvania; and Departments of.
Mohamed
M
Abdel-Mohsen
Blood Systems Research Institute, San Francisco, California, and.|University of California, San Francisco.
Satish K
SK
Pillai
Internal Medicine; and.
Sofie
S
Rutsaert
Internal Medicine; and.
Wim
W
Trypsteen
Internal Medicine; and.|Morphology, Faculty of Veterinary Medicine, Ghent University, Belgium.
Ward
W
De Spiegelaere
Internal Medicine; and.
Linos
L
Vandekerchove
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Lars
L
Østergaard
Department of Infectious Diseases, Aarhus University Hospital.
Thomas A
TA
Rasmussen
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Paul W
PW
Denton
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Martin
M
Tolstrup
Department of Infectious Diseases, Aarhus University Hospital.|Institute of Clinical Medicine, Aarhus University.
Ole S
OS
Søgaard
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000008:administration & dosage / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000187:drug effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D016898:Interferon-alpha / Q000097:blood / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D012367:RNA, Viral / Q000009:adverse effects / Q000097:blood; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics; D014766:Viremia / Q000097:blood / Q000188:drug therapy*; D017735:Virus Latency / Q000187:drug effects
D016207:Cytokines; D016898:Interferon-alpha; C000597235:MGN1703; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012367:RNA, Viral; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014452:Ubiquitins; C074034:ISG15 protein, human; D004247:DNA; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase
NK cell activation.; TLR9 agonist; immune therapeutic treatment; latency reversal; latent HIV-1 infection