Myristoylation as a target for inhibiting HIV assembly: unsaturated fatty acids block viral budding.
Modification of HIV-1 Gag with myristic acid, a saturated 14-carbon fatty acid (14:0), is essential for HIV-1 assembly. We recently showed that exogenous treatment of cells with unsaturated 14-carbon fatty acids, 5-cis-tetradecenoic acid (14:1n-9) and 5-cis,8-cis-tetradecadienoic acid (14:2n-6), reduces the affinity of some myristoylated proteins for plasma membrane rafts, membrane subdomains that have been shown to be required for efficient assembly of HIV. Here we demonstrate that treatment of cells with 14:1n-9 and 14:2n-6 fatty acids reduced the affinity of Gag for rafts but not membranes in general. Furthermore, treatment of cells with 14-carbon unsaturated fatty acids inhibited Gag-driven particle assembly. These effects most likely reflect covalent modification of Gag with unsaturated fatty acids. Treatment with 14:1n-9 and 14:2n-6 fatty acids did not alter intracellular protein trafficking, nor did it reduce cell viability. These studies suggest a strategy to attack HIV assembly by selectively altering the patterns of fatty acid modification.
Lindwasser
O Wolf
OW
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 143, New York, NY 10021, USA.
Resh
Marilyn D
MD
D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000494:pharmacology; D015683:Gene Products, gag / Q000737:chemistry* / Q000378:metabolism; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009227:Myristic Acids / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D005231:Fatty Acids, Unsaturated; D015683:Gene Products, gag; D008164:Luminescent Proteins; D009227:Myristic Acids; D011498:Protein Precursors; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; C108157:5,8-tetradecadienoic acid; D049452:Green Fluorescent Proteins