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Journal of Virology, August 2005, p. 10155-10163, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10155-10163.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Envelope Targeting: Hemagglutinin Attachment Specificity Rather than Fusion Protein Cleavage-Activation Restricts Tupaia Paramyxovirus Tropism

Christoph Springfeld,1 Veronika von Messling,1,{dagger} Christian A. Tidona,2 Gholamreza Darai,2 and Roberto Cattaneo1*

Molecular Medicine Program and Virology and Gene Therapy Track, Mayo College of Medicine, Rochester, Minnesota 55905,1 Hygiene-Institut der Universität Heidelberg, Abteilung Virologie, 69120 Heidelberg, Germany2

Received 8 March 2005/ Accepted 11 May 2005

To engineer a targeting envelope for gene and oncolytic vector delivery, we characterized and modified the envelope proteins of Tupaia paramyxovirus (TPMV), a relative of the morbilli- and henipaviruses that neither infects humans nor has cross-reactive relatives that infect humans. We completed the TPMV genomic sequence and noted that the predicted fusion (F) protein cleavage-activation site is not preceded by a canonical furin cleavage sequence. Coexpression of the TPMV F and hemagglutinin (H) proteins induced fusion of Tupaia baby fibroblasts but not of human cells, a finding consistent with the restricted TPMV host range. To identify the factors restricting fusion of non-Tupaia cells, we initially analyzed F protein cleavage. Even without an oligo- or monobasic protease cleavage sequence, TPMV F was cleaved in F1 and F2 subunits in human cells. Edman degradation of the F1 subunit yielded the sequence IFWGAIIA, placing the conserved phenylalanine in position 2, a novelty for paramyxoviruses but not the cause of fusion restriction. We then verified whether the lack of a TPMV H receptor limits fusion. Toward this end, we displayed a single-chain antibody (scFv) specific for the designated receptor human carcinoembryonic antigen on the TPMV H ectodomain. The H-scFv hybrid protein coexpressed with TPMV F mediated fusion of cells expressing the designated receptor, proving that the lack of a receptor limits fusion and that TPMV H can be retargeted. Targeting competence and the absence of antibodies in humans define the TPMV envelope as a module to be adapted for ferrying ribonucleocapsids of oncolytic viruses and gene delivery vectors.

* Corresponding author. Mailing address: Mayo Clinic Rochester, Molecular Medicine Program, Guggenheim 1838, 200 First St. SW, Rochester, MN 55902. Phone: (507) 284-0171. Fax: (507) 266-2122. E-mail: Cattaneo.Roberto{at}mayo.edu.

{dagger} Present address: INRS-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.

Journal of Virology, August 2005, p. 10155-10163, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10155-10163.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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