Recognition of virus infection and innate host responses to viral gene therapy vectors.
The innate immune and inflammatory response represents one of the key stumbling blocks limiting the efficacy of viral-based therapies. Numerous human diseases could be corrected or ameliorated if viruses were harnessed to safely and effectively deliver therapeutic genes to diseased cells and tissues in vivo. Recent studies have shown that host cells recognize viruses using an elaborate network of sensor proteins localized at the plasma membrane, in endosomes, or in the cytosol. Three classes of sensors have been implicated in sensing viruses in mammalian cells-Toll-like receptors (TLRs), retinoid acid-inducible gene (RIG)-I-like receptors (RLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs). The interaction of virus-associated nucleic acids with these sensor molecules triggers a signaling cascade that activates the principal host defense program aimed to limit or eliminate virus infection and restore tissue homeostasis. In addition, recent data strongly suggest that host cells can mount innate immune responses to viruses without prior recognition of their nucleic acids. To deliver therapeutic genes into the nuclei of diseased cells, viral gene therapy vectors must be efficient at penetrating either the plasma or endosomal membrane. The therapeutic use of high numbers of virus particles disturbs cellular homeostasis, triggering cell damage and stress pathways, or "sensing of modified self". Accumulating data indicate that the sensing of modified self might represent a powerful framework explaining the innate immune response activation by viral gene therapy vectors.
Shayakhmetov
Dmitry M
DM
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA. dshax@uw.edu
Di Paolo
Nelson C
NC
Mossman
Karen L
KL
D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014780:Viruses / Q000235:genetics*
D051193:Toll-Like Receptors