title: Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides.
abstract: 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.
authors.affiliation: Institute for Biomedical Research Georg-Speyer-Haus, Frankfurt a. M. Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Egelhofer
authors.forename: Gunda
authors.initials: G
authors.lastname: Brandenburg
authors.forename: Holger
authors.initials: H
authors.lastname: Martinius
authors.forename: Patricia
authors.initials: P
authors.lastname: Schult-Dietrich
authors.forename: Gregory
authors.initials: G
authors.lastname: Melikyan
authors.forename: Renate
authors.initials: R
authors.lastname: Kunert
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: Ingrid
authors.initials: I
authors.lastname: Choi
authors.forename: Alexander
authors.initials: A
authors.lastname: Alexandrov
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
mesh_terms: D000595:Amino Acid Sequence; D002459:Cell Fusion; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments