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Journal of Virology, August 2008, p. 7483-7491, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00295-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of Residues outside of the Receptor Binding Domain That Influence the Infectivity and Tropism of Porcine Endogenous Retrovirus{triangledown}

Takele Argaw,1 Mariel Figueroa,1 Daniel R. Salomon,2 and Carolyn A. Wilson1*

Gene Transfer and Immunogenicity Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, FDA, Building 29B, Room 5NN22, HFM 725, 8800 Rockville Pike, Bethesda, Maryland,1 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 930372

Received 9 February 2008/ Accepted 19 May 2008

Identification of determinants of human tropism of porcine endogenous retrovirus (PERV) is critical to understanding the risk of transmission of PERV to recipients of porcine xenotransplantation products. Previously, we showed that a chimeric envelope cDNA encoding the 360 N-terminal residues of the human-tropic PERV envelope class A (PERV-A) SU and the 130 C-terminal residues of the pig-tropic PERV-C SU and all of TM (PERV-A/C) showed a 100-fold decrease in infectivity titer on human cells (M. Gemeniano, O. Mpanju, D. R. Salomon, M. V. Eiden, and C. A. Wilson, Virology 346:108-117, 2006). To identify residues important for human cell infection, we performed site-directed mutagenesis on each of the nine residues, singly or in combination, that distinguish the C-terminal region of PERV-C from PERV-A. Of the nine amino acids, two single-amino-acid substitutions, Q374R and I412V, restored the infectivity of human cells to the chimeric PERV-A/C to a titer equivalent to that of PERV-A. In contrast, PERV-A/C mutant envelope Q439P resulted in undetectable infection of human cells and an approximately 1,000-fold decrease in control pig cells. Mutation of K441R rescued mutants that carried Q439P, suggesting an incompatibility between the proline residue at this position and the presence of KK in the proteolytic cleavage signal. We confirmed this incompatibility with vectors carrying PERV-A envelope mutant R462K that were also rendered noninfectious. Finally, tropism of vectors carrying PERV-C envelope mutants with only four amino acid changes in the C terminus of PERV-C envelope, NHRQ436YNRP plus K441R, was shifted to one similar to that of PERV-A. Our results show an important and previously unrecognized role for infectivity and tropism for residues at the C terminus of SU.

* Corresponding author. Mailing address: Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Bldg. 29B, Room 5NN22, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-0481. Fax: (301) 827-0449. E-mail: carolyn.wilson{at}fda.hhs.gov

{triangledown} Published ahead of print on 28 May 2008.

Journal of Virology, August 2008, p. 7483-7491, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00295-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mazari, P. M., Linder-Basso, D., Sarangi, A., Chang, Y., Roth, M. J. (2009). Single-round selection yields a unique retroviral envelope utilizing GPR172A as its host receptor. Proc. Natl. Acad. Sci. USA 106: 5848-5853 [Abstract] [Full Text]  


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