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Journal of Virology, January 2004, p. 568-575, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.568-575.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Entry in Cells Expressing gp41-Derived Peptides

Marc Egelhofer,1,{dagger} Gunda Brandenburg,1,{dagger} Holger Martinius,1 Patricia Schult-Dietrich,1 Gregory Melikyan,2 Renate Kunert,3 Christopher Baum,4 Ingrid Choi,1 Alexander Alexandrov,5 and Dorothee von Laer1*

Institute for Biomedical Research Georg-Speyer-Haus, Frankfurt a. M.,1 Medizinische Hochschule Hannover, Hannover,4 BioCore GmbH, Bad Homburg, Germany,5 Department of Physiology, Rush Medical College, Chicago, Illinois,2 Institute of Applied Microbiology, Vienna, Austria3

Received 12 March 2003/ Accepted 7 October 2003

As the limitations of antiretroviral drug therapy, such as toxicity and resistance, become evident, interest in alternative therapeutic approaches for human immunodeficiency virus (HIV) infection is growing. We developed the first gene therapeutic strategy targeting entry of a broad range of HIV type 1 (HIV-1) variants. Infection was inhibited at the level of membrane fusion by retroviral expression of a membrane-anchored peptide derived from the second heptad repeat of the HIV-1 gp41 transmembrane glycoprotein. To achieve maximal expression and antiviral activity, the peptide itself, the scaffold for presentation of the peptide on the cell surface, and the retroviral vector backbone were optimized. This optimized construct effectively inhibited virus replication in cell lines and primary blood lymphocytes. The membrane-anchored C-peptide was also shown to bind to free gp41 N peptides, suggesting that membrane-anchored antiviral C peptides have a mode of action similar to that of free gp41 C peptides. Preclinical toxicity and efficacy studies of this antiviral vector have been completed, and clinical trials are in preparation.

* Corresponding author. Mailing address: Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt a. M., Germany. Phone: 49-69-63395232. Fax: 49-69-63395297. E-mail: laer{at}em.uni-frankfurt.de.

{dagger} M.E. and G.B. contributed equally to this study.

Journal of Virology, January 2004, p. 568-575, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.568-575.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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