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Journal of Virology, March 2003, p. 3281-3290, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3281-3290.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

An Antiviral Peptide Targets a Coiled-Coil Domain of the Human T-Cell Leukemia Virus Envelope Glycoprotein

Josefina D. Piñón,1 Sharon M. Kelly,2 Nicholas C. Price,2 Jack U. Flanagan,1 and David W. Brighty1*

The Biomedical Research Centre, Ninewells Hospital and Medical School, The University, Dundee DD1 9SY,1 Division of Biochemistry and Molecular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom2

Received 22 August 2002/ Accepted 3 December 2002

Retrovirus entry into cells is mediated by the viral envelope glycoproteins which, through a cascade of conformational changes, orchestrate fusion of the viral and cellular membranes. In the absence of membrane fusion, viral entry into the host cell cannot occur. For human T-cell leukemia virus type 1 (HTLV-1), synthetic peptides that mimic a carboxy-terminal region of the transmembrane glycoprotein (TM) ectodomain are potent inhibitors of membrane fusion and virus entry. Here, we demonstrate that this class of inhibitor targets a fusion-active structure of HTLV-1 envelope. In particular, the peptides bind specifically to a core coiled-coil domain of envelope, and peptide variants that fail to bind the coiled-coil lack inhibitory activity. Our data indicate that the inhibitory peptides likely function by disrupting the formation of a trimer-of-hairpins structure that is required for membrane fusion. Importantly, we also show that peptides exhibiting dramatically increased potency can be readily obtained. We suggest that peptides or peptide mimetics targeting the fusion-active structures of envelope may be of therapeutic value in the treatment of HTLV-1 infections.

* Corresponding author. Mailing address: Biomedical Research Centre, Level 5 Ninewells Hospital, Dundee DD1 9SY, Scotland, United Kingdom. Phone: 44 (0) 1382 660111, ext. 33513. Fax: 44 (0) 1382 669993. E-mail: brighty{at}cancer.org.uk.

Journal of Virology, March 2003, p. 3281-3290, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3281-3290.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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