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Journal of Virology, June 2004, p. 5812-5819, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5812-5819.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Reduced Sensitivity to Human Serum Inactivation of Enveloped Viruses Produced by Pig Cells Transgenic for Human CD55 or Deficient for the Galactosyl-{alpha}(1-3) Galactosyl Epitope

Saema Magre,1 Yasuhiro Takeuchi,1* Gillian Langford,2 Andrew Richards,2 Clive Patience,3 and Robin Weiss1

Department of Immunology and Molecular Pathology, University College London, London,1 Imutran Ltd. (a Novartis Pharma A.G. Company), Cambridge, United Kingdom,2 Immerge BioTherapeutics Inc., Cambridge, Massachusetts3

Received 11 November 2003/ Accepted 29 January 2004

Complement activation mediated by the major xenogeneic epitope in the pig, galactosyl-{alpha}(1-3) galactosyl sugar structure ({alpha}-Gal), and human natural antibodies could cause hyperacute rejection (HAR) in pig-to-human xenotransplantation. The same reaction on viruses bearing {alpha}-Gal may serve as a barrier to zoonotic infection. Expressing human complement regulatory proteins or knocking out {alpha}-Gal epitopes in pig in order to overcome HAR may therefore pose an increased risk in xenotransplantation with regard to zoonosis. We investigated whether amphotropic murine leukemia virus, porcine endogenous retrovirus, and vesicular stomatitis virus (VSV) budding from primary transgenic pig aortic endothelial (TgPAE) cells expressing human CD55 (hCD55 or hDAF) was protected from human-complement-mediated inactivation. VSV propagated through the ST-IOWA pig cell line, in which {alpha}-galactosyl-transferase genes were disrupted (Gal null), was also tested for sensitivity to human complement. The TgPAE cells were positive for hCD55, and all pig cells except the Gal-null ST-IOWA expressed {alpha}-Gal epitopes. Through antibody binding, we were able to demonstrate the incorporation of hCD55 onto VSV particles. Viruses harvested from TgPAE cells were relatively resistant to complement-mediated inactivation by the three sources of human sera tested. Additionally, VSV from Gal-null pig cells was resistant to human complement inactivation. Such protection of enveloped viruses may increase the risk of zoonosis from pigs genetically modified for pig-to-human xenotransplantation.

* Corresponding author. Mailing address: Wohl Virion Centre, Windeyer Institute of Medical Sciences, University College London, 46 Cleveland St., London W1T 4JF, United Kingdom. Phone: 44 20 7679 9569. Fax: 44 20 7679 9555. E-mail: y.takeuchi{at}ucl.ac.uk.

Journal of Virology, June 2004, p. 5812-5819, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5812-5819.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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