Adenoviruses are promising vectors for therapeutic applications in humans. The striking discrepancy between profound phenotypes of Ad mutants, possessing modifications in individual capsid proteins, and our inability to selectively target tumor cells after intravascular virus delivery underscores poorly appreciated redundancy and overlap of molecular pathways, which become engaged when virus is delivered via intravascular route. This proposal is to conduct comprehensive mechanistic studies to define the contribution of each of the major structural elements of the Ad capsid in mediating virus interaction with liver cells in vivo. Using a large set of previously constructed capsid- modified Ad vectors, we will analyze the role of 1) the fiber structure;2) the penton-host integrin interactions;and 3) the hexon-blood factor interactions in mediating Ad trapping in the liver and hepatocyte transduction after intravascular Ad delivery. Based on the accumulated data we will 4) construct a lung carcinoma cell-targeted oncolytic Ad vector that escapes trapping by the liver and evaluate its anti-tumor efficacy in a mouse model. These studies will dramatically improve our understanding of the mechanisms governing Ad-host interactions in vivo and will ultimately lead to the development of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.

Public Health Relevance

Adenovirus vectors (Ad) are the most common viral vector type used in clinical studies worldwide. Despite extensive use in gene transfer applications as well as vaccinations against life threatening infectious agents, Ad's use as an anti-cancer therapeutic is greatly impeded due to poor understanding of the molecular mechanisms that govern virus infectivity and bio-distribution in vivo. Ad liver cell transduction causes clinically significant hepatotoxicity and complicates strategies for Ad targeting to disseminated metastatic tumor cells in vivo. This proposal is to fill the major void in our understanding of Ad interactions with host cells and factors in vivo. These studies will ultimately lead to the development of a first panel of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Daschner, Phillip J
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Di Paolo, Nelson C; Baldwin, Lisa K; Irons, Eric E et al. (2014) IL-1? and complement cooperate in triggering local neutrophilic inflammation in response to adenovirus and eliminating virus-containing cells. PLoS Pathog 10:e1004035
Di Paolo, Nelson C; Shayakhmetov, Dmitry M (2014) The analysis of innate immune response to adenovirus using antibody arrays. Methods Mol Biol 1089:133-41
Di Paolo, Nelson C; Doronin, Konstantin; Baldwin, Lisa K et al. (2013) The transcription factor IRF3 triggers ""defensive suicide"" necrosis in response to viral and bacterial pathogens. Cell Rep 3:1840-6
Irons, Eric E; Flatt, Justin W; Doronin, Konstantin et al. (2013) Coagulation factor binding orientation and dimerization may influence infectivity of adenovirus-coagulation factor complexes. J Virol 87:9610-9
Di Paolo, Nelson C; Shayakhmetov, Dmitry M (2013) Interleukin-1 receptor 2 keeps the lid on interleukin-1?. Immunity 38:203-5
Doronin, Konstantin; Shayakhmetov, Dmitry M (2012) Construction of targeted and armed oncolytic adenoviruses. Methods Mol Biol 797:35-52
Doronin, Konstantin; Flatt, Justin W; Di Paolo, Nelson C et al. (2012) Coagulation factor X activates innate immunity to human species C adenovirus. Science 338:795-8
Woetzel, Nils; Lindert, Steffen; Stewart, Phoebe L et al. (2011) BCL::EM-Fit: rigid body fitting of atomic structures into density maps using geometric hashing and real space refinement. J Struct Biol 175:264-76
Shayakhmetov, Dmitry M; Di Paolo, Nelson C; Mossman, Karen L (2010) Recognition of virus infection and innate host responses to viral gene therapy vectors. Mol Ther 18:1422-9
Di Paolo, Nelson C; van Rooijen, Nico; Shayakhmetov, Dmitry M (2009) Redundant and synergistic mechanisms control the sequestration of blood-born adenovirus in the liver. Mol Ther 17:675-84

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