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Journal of Virology, August 1999, p. 6923-6929, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Retrovirus Targeting by Tropism Restriction to Melanoma Cells

F. Martin,1 S. Neil,1 J. Kupsch,2 M. Maurice,3 F.-L. Cosset,3 and M. Collins1,*

Department of Immunology, Windeyer Institute for Medical Science, University College London, London,1 and Mount Vernon Hospital, RAFT Laboratories, Northwood, Middlesex,2 United Kingdom, and Centre de Genetique Moleculaire et Cellulaire, CNRS UMR5534, UCB Lyon-1, France3

Received 22 February 1999/Accepted 10 May 1999

Targeted vectors will be necessary for many gene therapy applications. To target retroviruses to melanomas, we fused a single-chain variable fragment antibody (scFv) directed against the surface glycoprotein high-molecular-weight melanoma-associated antigen (HMW-MAA) to the amphotropic murine leukemia virus envelope. A proline-rich hinge and matrix metalloprotease (MMP) cleavage site linked the two proteins. The modified viruses bound only to HMW-MAA-expressing cells, as inclusion of the proline-rich hinge prevented viral binding to the amphotropic viral receptor. Following attachment to HMW-MAA, MMP cleavage of the envelope at the melanoma cell surface removed the scFv and proline-rich hinge, allowing infection. Complexing of targeted retroviruses with 2,3-dioleoyloxy-N-[2(spermine-carboxamido)ethyl]N,N-dimethyl-1-propanaminium trifluoroacetate-dioleoyl phosphatidylethanolamine liposomes greatly increased their efficiency without affecting their target cell specificity. In a cell mixture, 40% of HMW-MAA-positive cells but less than 0.01% of HMW-MAA-negative cells were infected. This approach can therefore produce efficient, targeted retroviruses suitable for in vivo gene delivery and should allow specific gene delivery to many human cell types by inclusion of different scFv and protease combinations.

* Corresponding author. Mailing address: Department of Immunology, Windeyer Institute for Medical Science, University College London, 46 Cleveland St., London W1P 6DB, United Kingdom. Phone and Fax: 44-171-504-9301. E-mail: mary.collins{at}ucl.ac.uk.

Journal of Virology, August 1999, p. 6923-6929, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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