Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides.
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.
Egelhofer
Marc
M
Institute for Biomedical Research Georg-Speyer-Haus, Frankfurt a. M. Medizinische Hochschule Hannover, Hannover, Germany.
Brandenburg
Gunda
G
Martinius
Holger
H
Schult-Dietrich
Patricia
P
Melikyan
Gregory
G
Kunert
Renate
R
Baum
Christopher
C
Choi
Ingrid
I
Alexandrov
Alexander
A
von Laer
Dorothee
D
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
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments