Abstract
Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag’s N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMAQ5A/G6S). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P2 cellular signaling system to direct intracellular Gag trafficking during virus assembly.
Highlights
Of human immunodeficiency virus (HIV) particles occurs by a complex, multistep mechanism that includes temporally and spatially dependent interactions with several cellular host factors at or near the plasma membrane (PM) [1,2,3,4,5,6]
These results suggest that the assembly and release of feline immunodeficiency virus (FIV) particles from feline cells is highly sensitive to PM levels of PI(4,5)P2, similar to HIV-1 and HIV-2 [14,24]
Guillon and co-workers showed that the FIV myr(-)MA adopts a highly helical three dimensional structure that is similar to structures observed previously by NMR and X-ray crystallography for the HIV-1 and HIV-2 myr(-)MA and myrMA proteins [17,24,44,46,48,68,69]
Summary
Of human immunodeficiency virus (HIV) particles occurs by a complex, multistep mechanism that includes temporally and spatially dependent interactions with several cellular host factors at or near the plasma membrane (PM) [1,2,3,4,5,6]. The viral envelope of HIV-1 is enriched in phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], cholesterol, and lipid constituents associated with lipid raft-like microdomains [7,8,9,10,11,12,13], indicating that virus assembly occurs in rafts. Induction of PI(4,5)P2-enriched endosomes can retarget Gag to endosomes and MVBs and induce intravesicle budding, and substitution of HIV-1 MA by the membrane-binding N terminus of Fyn kinase reduces the sensitivity of virus assembly to PI(4,5)P2 manipulation. These studies collectively indicate that PI(4,5)P2-dependent membrane selection is mediated by the MA domain of Gag [14]. In vitro binding assays with other lipid constituents containing truncated acyl chains have led to proposals that phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine may bind HIV-1 myrMA in extended lipid conformations, and thereby help target Gag to PM rafts [25]
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