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Journal of Virology, November 2006, p. 10634-10644, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01359-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Fiber and Penton Base Capsid Modifications Yield Diminished Adenovirus Type 5 Transduction and Proinflammatory Gene Expression with Retention of Antigen-Specific Humoral Immunity{triangledown}

John W. Schoggins and Erik Falck-Pedersen*

Weill Medical College of Cornell University, Hearst Research Foundation, Department of Microbiology and Immunology, Molecular Biology Graduate Program, New York, New York 10021

Received 27 June 2006/ Accepted 17 August 2006

Fiber and penton base capsid proteins of adenovirus type 5 (Ad5) mediate a well-characterized two-step entry pathway in permissive tissue culture cell lines. Fiber binds with high affinity to the cell surface coxsackievirus-and-adenovirus receptor (CAR), and penton base facilitates viral internalization by binding {alpha}v integrins through an RGD motif. In vivo, the entry pathway is complicated by interactions of capsid proteins with additional cell surface molecules and blood factors. When administered systemically in mice, adenovirus vectors (Adv) localize primarily to hepatic tissue, resulting in efficient gene transduction and potent activation of the host antiviral immune response. The goal of the present study was to detarget Adv uptake through fiber and penton base capsid protein manipulations and determine how detargeted vectors influence transduction efficiency, inflammatory activation, and activation of the adaptive arm of the immune system. By manipulating fiber and the penton base, we have generated highly detargeted vectors (up to 1,200-fold reduction in transgene expression in vivo) with reduced macrophage stimulatory activity in vitro and in vivo. In spite of the diminished transduction and macrophage activation, the detargeted vectors induce strong neutralizing immunity as well as efficient antitransgene antibody. Three of the modified vectors produce antitransgene humoral immunity at levels that exceed or are equal to that seen with an unmodified Ad5-based vector. The fiber-pseudotyped and penton base constructs with RGD deleted have attributes that could be important enhancements in a number of vaccine applications.

* Corresponding author. Mailing address: Weill Medical College of Cornell University, Department of Microbiology and Immunology Box 62, 1300 York Ave., New York, NY 10021. Phone: (212) 746-6514. Fax: (212) 746-8587. E-mail: efalckp{at}med.cornell.edu.

{triangledown} Published ahead of print on 30 August 2006.

Journal of Virology, November 2006, p. 10634-10644, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01359-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nociari, M., Ocheretina, O., Murphy, M., Falck-Pedersen, E. (2009). Adenovirus Induction of IRF3 Occurs through a Binary Trigger Targeting Jun N-Terminal Kinase and TBK1 Kinase Cascades and Type I Interferon Autocrine Signaling. J. Virol. 83: 4081-4091 [Abstract] [Full Text]  
  • Nociari, M., Ocheretina, O., Schoggins, J. W., Falck-Pedersen, E. (2007). Sensing Infection by Adenovirus: Toll-Like Receptor-Independent Viral DNA Recognition Signals Activation of the Interferon Regulatory Factor 3 Master Regulator. J. Virol. 81: 4145-4157 [Abstract] [Full Text]  


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