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 Blood, 26 February 2009, Vol. 113, No. 9, pp. 1909-1918.
Prepublished online as a Blood First Edition Paper on January 8, 2009; DOI 10.1182/blood-2008-09-178459.

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GENE THERAPY

Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1

Robert C. Carlisle1, Ying Di1, Anna M. Cerny2, Andreas F.-P. Sonnen3, Robert B. Sim4, Nicola K. Green5, Vladimir Subr6, Karel Ulbrich6, Robert J. C. Gilbert3, Kerry D. Fisher1, Robert W. Finberg2, and Leonard W. Seymour1

1 Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom; 2 Department of Medicine, University of Massachusetts Medical School, Worcester; 3 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; 4 Medical Research Council Immunohistochemistry Unit, University of Oxford, Oxford, United Kingdom; 5 Hybrid Systems, Cherwell Innovation Centre, Upper Heyford, United Kingdom; and 6 Institute of Macromolecular Chemistry, Academy of Science of the Czech Republic, Prague, Czech Republic

Type 5 adenovirus (Ad5) is a human pathogen that has been widely developed for therapeutic uses, with only limited success to date. We report here the novel finding that human erythrocytes present Coxsackie virus-adenovirus receptor (CAR) providing an Ad5 sequestration mechanism that protects against systemic infection. Interestingly, erythrocytes from neither mice nor rhesus macaques present CAR. Excess Ad5 fiber protein or anti-CAR antibody inhibits the binding of Ad5 to human erythrocytes and cryo-electron microscopy shows attachment via the fiber protein of Ad5, leading to close juxtaposition with the erythrocyte membrane. Human, but not murine, erythrocytes also present complement receptor (CR1), which binds Ad5 in the presence of antibodies and complement. Transplantation of human erythrocytes into nonobese diabetic/severe combined immunodeficiency mice extends blood circulation of intravenous Ad5 but decreases its extravasation into human xenograft tumors. Ad5 also shows extended circulation in transgenic mice presenting CAR on their erythrocytes, although it clears rapidly in transgenic mice presenting erythrocyte CR1. Hepatic infection is inhibited in both transgenic models. Erythrocytes may therefore restrict Ad5 infection (natural and therapeutic) in humans, independent of antibody status, presenting a formidable challenge to Ad5 therapeutics. "Stealthing" of Ad5 using hydrophilic polymers may enable circumvention of these natural virus traps.


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