Membrane-anchored inhibitory peptides capture human immunodeficiency virus type 1 gp41 conformations that engage the target membrane prior to fusion

Journal of Virology
Gregory B MelikyanD von Laer

Abstract

Soluble peptides derived from the C-terminal heptad repeat domain of human immunodeficiency virus type 1 (HIV-1) gp41 are potent inhibitors of HIV-1 entry and gp41-induced fusion. Target membrane-anchored variants of these peptides have been shown to retain inhibitory activity. Both soluble and membrane-anchored C peptides (MACs) are thought to block fusion by binding to the N-terminal coiled coil domain of gp41 and preventing formation of the final six-helix bundle structure. However, interactions of target MACs with gp41 must be restricted to a subset of trimers that have their hydrophobic fusion peptides inserted into the target membrane. This unique feature of MACs was used to identify the intermediate step of fusion at which gp41 engaged the target membrane. Fusion between HIV envelope-expressing effector cells and target cells was measured by fluorescence microscopy. Expression of MACs in target cells led to less than twofold reduction in the extent of fusion. However, when reaction was first arrested by adding lysolipids that disfavored membrane merger, and the lipids were subsequently removed by washing, control cells supported fusion, whereas those that expressed MACs did not. The drastically improved potency of MACs i...Continue Reading

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Citations

Jan 1, 2010·Nature Reviews. Drug Discovery·Lawrence RajendranKai Simons
Jul 8, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yael Wexler-CohenYechiel Shai
Aug 9, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Avraham AshkenaziYechiel Shai
Aug 21, 2014·Journal of Medical Primatology·Andrew G MacLeanStephen E Braun
Jul 19, 2011·Biochimica Et Biophysica Acta·Avraham AshkenaziYechiel Shai
Feb 20, 2014·Proceedings of the National Academy of Sciences of the United States of America·Julien RocheAdriaan Bax
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Jun 19, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yael Wexler-Cohen, Yechiel Shai
Jun 19, 2013·Molecular BioSystems·Miriam Avadisian, Patrick T Gunning

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