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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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Submitted September 12, 2008
Accepted November 7, 2008
Human erythrocytes bind and inactivate type 5 adenovirus by presenting coxsackievirus-adenovirus receptor and complement receptor 1
Robert C. Carlisle*, Ying Di, Anna M. Cerny, Andreas F-P. Sonnen, Robert B. Sim, Nicola K. Green, Vladimir Subr, Karel Ulbrich, Robert J.C. Gilbert, Kerry D. Fisher, Robert W. Finberg, and Leonard W. Seymour
Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom
MRC Immunohistochemistry Unit, University of Oxford, Oxford, United Kingdom
Hybrid Systems Ltd, Oxfordshire, United Kingdom
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
* Corresponding author; email: robert.carlisle{at}clinpharm.ox.ac.uk.
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 Coxsackievirus-Adenovirus receptor (CAR) providing an Ad5 sequestration mechanism which protects against systemic infection. Interestingly, erythrocytes from neither mice nor rhesus macaques present CAR. Excess Ad5 fibre protein or anti-CAR antibody inhibits the binding of Ad5 to human erythrocytes and cryoEM shows attachment via the fibre 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 NOD-SCID mice extends blood circulation of intravenous Ad5, but decreases its extravasation into human xenograft tumours. 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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