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@ARTICLE{Vragniau:120552,
      author       = {C. Vragniau and J.-M. Hübner$^*$ and P. Beidler and S. Gil
                      and K. Saydaminova and Z.-Z. Lu and R. Yumul and H. Wang and
                      M. Richter and P. Sova and C. Drescher and P. Fender and A.
                      Lieber},
      title        = {{S}tudies on the {I}nteraction of {T}umor-{D}erived {HD}5
                      {A}lpha {D}efensins with {A}denoviruses and {I}mplications
                      for {O}ncolytic {A}denovirus {T}herapy.},
      journal      = {Journal of virology},
      volume       = {91},
      number       = {6},
      issn         = {1098-5514},
      address      = {Baltimore, Md.},
      publisher    = {Soc.},
      reportid     = {DKFZ-2017-00981},
      pages        = {e02030-16 -},
      year         = {2017},
      abstract     = {Defensins are small antimicrobial peptides capable of
                      neutralizing human adenovirus (HAdV) in vitro by binding
                      capsid proteins and blocking endosomal escape of virus. In
                      humans, the alpha defensin HD5 is produced by specialized
                      epithelial cells of the gastrointestinal and genito-urinary
                      tracts. Here, we demonstrate, using patient biopsy
                      specimens, that HD5 is also expressed as an active, secreted
                      peptide by epithelial ovarian and lung cancer cells in situ
                      This finding prompted us to study the role of HD5 in
                      infection and spread of replication-competent, oncolytic
                      HAdV type 3 (HAdV3). HAdV3 produces large amounts of
                      penton-dodecahedra (PtDd), virus-like particles, during
                      replication. We have previously shown that PtDd are involved
                      in opening epithelial junctions, thus facilitating lateral
                      spread of de novo-produced virions. Here, we describe a
                      second function of PtDd, namely, the blocking of HD5. A
                      central tool to prove that viral PtDd neutralize HD5 and
                      support spread of progeny virus was an HAdV3 mutant virus in
                      which formation of PtDd was disabled (mut-Ad3GFP, where GFP
                      is green fluorescent protein). We demonstrated that viral
                      spread of mut-Ad3GFP was blocked by synthetic HD5 whereas
                      that of the wild-type (wt) form (wt-Ad3GFP) was only
                      minimally impacted. In human colon cancer Caco-2 cells,
                      induction of cellular HD5 expression by fibroblast growth
                      factor 9 (FGF9) significantly inhibited viral spread and
                      progeny virus production of mut-Ad3GFP but not of wt-Ad3GFP.
                      Finally, the ectopic expression of HD5 in tumor cells
                      diminished the in vivo oncolytic activity of mut-Ad3GFP but
                      not of wt-Ad3GFP. These data suggest a new mechanism of
                      HAdV3 to overcome innate antiviral host responses. Our study
                      has implications for oncolytic adenovirus therapy.IMPORTANCE
                      Previously, it has been reported that human defensin HD5
                      inactivates specific human adenoviruses by binding to capsid
                      proteins and blocking endosomal escape of virus. The central
                      new findings described in our manuscript are the following:
                      (i) the discovery of a new mechanism used by human
                      adenovirus serotype 3 to overcome innate antiviral host
                      responses that is based on the capacity of HAdV3 to produce
                      subviral penton-dodecahedral particles that act as decoys
                      for HD5, thus preventing the inactivation of virus progeny
                      produced upon replication; (ii) the demonstration that
                      ectopic HD5 expression in cancer cells decreases the
                      oncolytic efficacy of a serotype 5-based adenovirus vector;
                      and (iii) the demonstration that epithelial ovarian and lung
                      cancers express HD5. The study improves our understanding of
                      how adenoviruses establish infection in epithelial tissues
                      and has implications for cancer therapy with oncolytic
                      adenoviruses.},
      keywords     = {alpha-Defensins (NLM Chemicals) / alpha-defensin 5, human
                      (NLM Chemicals)},
      cin          = {B062},
      ddc          = {570},
      cid          = {I:(DE-He78)B062-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28077642},
      pmc          = {pmc:PMC5331826},
      doi          = {10.1128/JVI.02030-16},
      url          = {https://inrepo02.dkfz.de/record/120552},
}