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Journal of Virology, December 2004, p. 13871-13879, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13871-13879.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Determinants of High Titer in Recombinant Porcine Endogenous Retroviruses

Ian Harrison,1 Yasuhiro Takeuchi,2 Birke Bartosch,2,3 and Jonathan P. Stoye1*

National Institute for Medical Research,1 Wohl Virion Centre, Division of Infection and Immunity, University College London, London, United Kingdom,2 Laboratoire de Vecterologie Rétrovirale et Thérapie Génique, Institut National de la Santé et de la Recherche Médicale U412, IFR 128, Ecole Normale Supérieure de Lyon, Lyon, France3

Received 9 June 2004/ Accepted 3 August 2004

Porcine endogenous retroviruses (PERVs) pose a potential stumbling block for therapeutic xenotransplantation, with the greatest threat coming from viruses generated by recombination between members of the PERV subgroup A (PERV-A) and PERV-C families (PERV-A/C recombinants). PERV-A and PERV-B have been shown to infect human cells in culture, albeit with low titers. PERV-C has a more restricted host range and cannot infect human cells. A recombinant PERV-A/C virus (PERV-A14/220) contains the PERV-A sequence between the end of pol and the middle of the SU region in env. The remaining sequence is derived from PERV-C. PERV-A14/220 is approximately 500-fold more infectious than PERV-A. To determine the molecular basis for the increased infectivity of PERV-A14/220, we have made a series of vector constructs. The primary determinant for the enhanced replicative potential of the recombinant virus appeared to be the env gene. Using a series of chimeric env genes, we could identify two determinants of high infectivity; one was an isoleucine to valine substitution at position 140 between variable regions A and B, and the other lies within the proline rich region. Taken together, these results show that the novel juxtaposition of env gene sequences enhanced the infectivity of PERV-A14/220 for human cells, perhaps by stabilization of the envelope glycoprotein or increased receptor binding.

* Corresponding author. Mailing address: Medical Research Council, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 44 208 816 2140. Fax: 44 208 906 4477. E-mail: jstoye{at}nimr.mrc.ac.uk.

Journal of Virology, December 2004, p. 13871-13879, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13871-13879.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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