2. Academic Validation
  3. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA

Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA

  • Nat Immunol. 2015 Oct;16(10):1025-33. doi: 10.1038/ni.3267.
Anna-Maria Herzner 1,  Cristina Amparo Hagmann 1,  Marion Goldeck 1,  Steven Wolter 1,  Kirsten Kübler 2,  Sabine Wittmann 3,  Thomas Gramberg 3,  Liudmila Andreeva 4,  Karl-Peter Hopfner 4,  Christina Mertens 1,  Thomas Zillinger 1 5,  Tengchuan Jin 6,  Tsan Sam Xiao 7,  Eva Bartok 1,  Christoph Coch 1,  Damian Ackermann 8,  Veit Hornung 9,  Janos Ludwig 1,  Winfried Barchet 1 5,  Gunther Hartmann 1,  Martin Schlee 1
Affiliations

Affiliations

  • 1 Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
  • 2 Department of Obstetrics and Gynecology, Center for Integrated Oncology, University of Bonn, Bonn, Germany.
  • 3 Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
  • 4 Department Biochemistry, Gene Center, Ludwig-Maximilians University, Munich, Germany.
  • 5 German Center of Infectious Disease, Cologne-Bonn, Germany.
  • 6 School of Life Sciences, University of Science and Technology of China, Hefei, China.
  • 7 Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
  • 8 LIMES Institute, Chemical Biology, University of Bonn, Bonn, Germany.
  • 9 Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
PMID: 26343537 DOI: 10.1038/ni.3267
Abstract

Cytosolic DNA that emerges during Infection with a retrovirus or DNA virus triggers Antiviral type I interferon responses. So far, only double-stranded DNA (dsDNA) over 40 base pairs (bp) in length has been considered immunostimulatory. Here we found that unpaired DNA nucleotides flanking short base-paired DNA stretches, as in stem-loop structures of single-stranded DNA (ssDNA) derived from human immunodeficiency virus type 1 (HIV-1), activated the type I interferon-inducing DNA sensor cGAS in a sequence-dependent manner. DNA structures containing unpaired guanosines flanking short (12- to 20-bp) dsDNA (Y-form DNA) were highly stimulatory and specifically enhanced the enzymatic activity of cGAS. Furthermore, we found that primary HIV-1 reverse transcripts represented the predominant viral cytosolic DNA species during early Infection of macrophages and that these ssDNAs were highly immunostimulatory. Collectively, our study identifies unpaired guanosines in Y-form DNA as a highly active, minimal cGAS recognition motif that enables detection of HIV-1 ssDNA.

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