Phosphorothioate oligonucleotides inhibit human immunodeficiency virus type 1 fusion by blocking gp41 core formation.
Several studies have shown that phosphorothioate oligodeoxynucleotides (PS-ONs) have a sequence-independent antiviral activity against human immunodeficiency virus type 1 (HIV-1). It has also been suggested that PS-ONs inhibit HIV-1 by acting as attachment inhibitors that bind to the V3 loop of gp120 and prevent the gp120-CD4 interaction. Here we show that PS-ONs (and their fully 2'-O-methylated derivatives) are potent inhibitors of HIV-1-mediated membrane fusion and HIV-1 replication in a size-dependent, phosphorothioation-dependent manner. PS-ONs interact with a peptide derived from the N-terminal heptad repeat region of gp41, and the HIV-1 fusion-inhibitory activity of PS-ONs is closely correlated with their ability to block gp41 six-helix bundle formation, a critical step during the process of HIV-1 fusion with the target cell. These results suggest that the increased hydrophobicity of PS-ONs may contribute to their inhibitory activity against HIV-1 fusion and entry, because longer PS-ONs (>or=30 bases) which have a greater hydrophobicity are more potent in blocking the hydrophobic interactions involved in the gp41 six-helix bundle formation and inhibiting the HIV-1-mediated cell-cell fusion than shorter PS-ONs (<30 bases). This novel antiviral mechanism of action of long PS-ONs has implications for therapy against infection by HIV-1 and other enveloped viruses with type I fusion proteins.
Vaillant
Andrew
A
REPLICor Inc., 500 Cartier Blvd. West, Suite 135, Laval, QC, Canada H7V5B7. availlant@replicor.com
Juteau
Jean-Marc
JM
Lu
Hong
H
Liu
Shuwen
S
Lackman-Smith
Carol
C
Ptak
Roger
R
Jiang
Shibo
S
D002460:Cell Line; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects; D009841:Oligonucleotides / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D009841:Oligonucleotides; D013873:Thionucleotides