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Journal of Virology, July 2000, p. 5754-5761, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Feline Leukemia Virus Envelope Sequences That Affect T-Cell Tropism and Syncytium Formation Are Not Part of Known Receptor-Binding Domainsdagger

Samuel R. Gwynn,1,Dagger F. Claire Hankenson,2,3,4 Adam S. Lauring,1,4 Jennifer L. Rohn,3,§ and Julie Overbaugh3,4,*

Program in Molecular and Cellular Biology1 and Departments of Comparative Medicine2 and Microbiology,3 University of Washington, and Division of Human Biology, Fred Hutchinson Cancer Research Center,4 Seattle, Washington

Received 19 January 2000/Accepted 31 March 2000

The envelope protein is a primary pathogenic determinant for T-cell-tropic feline leukemia virus (FeLV) variants, the best studied of which is the immunodeficiency-inducing virus, 61C. We have previously demonstrated that T-cell-tropic, cytopathic, and syncytium-inducing viruses evolve in cats infected with a relatively avirulent, transmissible form of FeLV, 61E. The envelope gene of an 81T variant, which encoded scattered single-amino-acid changes throughout the envelope as well as a 4-amino-acid insertion in the C-terminal half of the surface unit (SU) of envelope, was sufficient to confer the T-cell-tropic, cytopathic phenotype (J. L. Rohn, M. S. Moser, S. R. Gwynn, D. N. Baldwin, and J. Overbaugh, J. Virol. 72:2686-2696, 1998). In the present study, we examined the role of the 4-amino-acid insertion in determining viral replication and tropism of FeLV-81T. The 4-amino-acid insertion was found to be functionally equivalent to a 6-amino-acid insertion at an identical location in the 61C variant. However, viruses expressing a chimeric 61E/81T SU, containing the insertion together with the N terminus of 61E SU, were found to be replication defective and were impaired in the processing of the envelope precursor into the functional SU and transmembrane (TM) proteins. In approximately 10% of cultured feline T cells (3201) transfected with the 61E/81T envelope chimeras and maintained over time, replication-competent tissue culture-adapted variants were isolated. Compensatory mutations in the SU of the tissue culture-adapted viruses were identified at positions 7 and 375, and each was shown to restore envelope protein processing when combined with the C-terminal 81T insertion. Unexpectedly, these viruses displayed different phenotypes in feline T cells: the virus with a change from glutamine to proline at position 7 acquired a T-cell-tropic, cytopathic phenotype, whereas the virus with a change from valine to leucine at position 375 had slower replication kinetics and caused no cytopathic effects. Given the differences in the replication properties of these viruses, it is noteworthy that the insertion as well as the two single-amino-acid changes all occur outside of predicted FeLV receptor-binding domains.

* Corresponding author. Mailing address: Division of Human Biology, Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., C3-168, Seattle, WA 98109-1024. Phone: (206) 667-3524. Fax: (206) 667-1535. E-mail: joverbau{at}fhcrc.org.

dagger This paper is dedicated to the memory of our friend and colleague, Samuel Rudolph Gwynn.

Dagger Deceased.

§ Present address: Leadd BV, 2300 AA Leiden, The Netherlands.

Journal of Virology, July 2000, p. 5754-5761, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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