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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

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.

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