Inhibition of HIV-1 Replication by Amphotericin B Methyl Ester

Waheed, Abdül; Ablan, Sherimay D.; Mankowski, Marie K.; Cummins, James E.; Ptak, Roger G.; Schaffner, Carl P.; Freed, Eric O.

doi:10.1074/jbc.m603609200

Cited by 60 publications

(85 citation statements)

References 72 publications

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“…This is supported by the observation that nystatin affected properties of the arginine and glucose transporters in yeast plasma membrane vesicles (20). Further, the amphotericin B methyl ester inhibited the replication, assembly, and release of HIV-1 by interfering with the ion channel viral protein U (VPU) (18,21). Microarray studies with S. cerevisiae clearly show an increase of expression of transport proteins on treatment with the polyenes amphotericin B and nystatin (22,23).…”

Section: Discussionsupporting

confidence: 56%

“…Answering the question of how natamycin changes the membrane properties starts with the premise that the antibiotic action is attributable to binding to ergosterol (7), thereby affecting the functional properties the sterol has on membrane proteins either via ergosterol-rich domains (17) or more directly by interfering with a direct ergosterol-protein interaction. The different oxygen functions of natamycin may play a role in the latter mechanism, as is also suggested for other polyenes (6,18). A disruption of the equilibrium of free sterols to sphingolipids by natamycin may also be responsible for the inhibition of ergosterol-dependent protein functions because sterols and sphingolipids work together to carry out a wide variety of functions (19).…”

Section: Discussionmentioning

confidence: 93%

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Polyene antibiotic that inhibits membrane transport proteins

Welscher

Leeuwen

Kruijff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 93%

Polyene antibiotic that inhibits membrane transport proteins

Welscher

Leeuwen

Kruijff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…SIV Env and HIV Env have remarkably long cytoplasmic domains. It has been recently reported that the second-site reversion mutants of SIV and HIV-1 that were resistant to amphotericin B methyl ester (AME), a cholesterol-binding compound, had truncated Env cytoplasmic domains (36). It was suggested that the truncated protein had a higher potential for movement in the lipid bilayer, which resulted in the escape from inhibition by AME.…”

Section: Msd Core Mutant Viruses Show Defects In Infectivitymentioning

confidence: 99%

Role of the Membrane-Spanning Domain of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein in Cell-Cell Fusion and Virus Infection

Liu

Yue

Hunter

2008

J Virol

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The membrane-spanning domain (MSD) of the human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein is critical for its biological activity. Previous C-terminal truncation studies have predicted an almost invariant core structure of 12 amino acid residues flanked by basic amino acids in the HIV-1 MSD that function to anchor the glycoprotein in the lipid bilayer. To further understand the role of specific amino acids within the MSD core, we initially replaced the core region with 12 leucine residues and then constructed recovery-of-function mutants in which specific amino acid residues (including a GGXXG motif) were reintroduced. We show here that conservation of the MSD core sequence is not required for normal expression, processing, intracellular transport, and incorporation into virions of the envelope glycoprotein (Env). However, the amino acid composition of the MSD core does influence the ability of Env to mediate cell-cell fusion and plays a critical role in the infectivity of HIV-1. Replacement of conserved amino acid residues with leucine blocked virus-to-cell fusion and subsequent viral entry into target cells. This restriction could not be released by C-terminal truncation of the gp41 glycoprotein. These studies imply that the highly conserved core residues of the HIV Env MSD, in addition to serving as a membrane anchor, play an important role in mediating membrane fusion during viral entry.The envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is a trimeric complex composed of three noncovalently linked dimers of gp120, the receptor-binding surface (SU) component, and gp41, the membrane-spanning, transmembrane (TM) component (8,21,43,44). The gp120 and gp41 glycoproteins are synthesized as a precursor gp160 glycoprotein, which is encoded by the env gene. The gp160 precursor is cotranslationally glycosylated and, following transport to the trans-Golgi network, is cleaved into the mature products by a member of the furin family of endoproteases (44). Mature Env proteins are transported to the plasma membrane, where they are rapidly endocytosed or incorporated into virions (1,28,42). Recent evidence suggests that endocytosis and intracellular trafficking of Env are required for its interaction with Gag precursors and for efficient assembly into virions (16).The gp41 monomer has three subdomains, i.e., an ectodomain, a membrane-spanning domain (MSD), and a cytoplasmic domain (39). The ectodomain of gp41, which mediates membrane fusion, is composed of a fusion peptide, two heptad repeats, and a tryptophan-rich membrane-proximal external region. Following the binding of gp120 to the CD4 receptor and CCR5/CXCR4 coreceptor, conformational changes are induced in Env and result in the exposure of the gp41 fusion peptide (27). This peptide inserts into the target cell membrane, allowing gp41 to form a bridge between the viral and cellular membranes. Interaction of the heptad repeats to form a six-helix bundle then brings the target and viral membranes together, allowing membrane fusio...

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“…It is intriguing that TIP47 possesses a hydrophobic cleft of dimensions comparable to those of the hydrophobic CsA-binding site on CypA (19). Additionally, gp41 cytoplasmic tail truncations rescue HIV-1 replication from the antiviral compound amphotericin B methyl ester (34). Taken together, these observations prompted us to determine if gp41 cytoplasmic tail mutants would rescue HIV-1 from the CsAinduced defects in Env incorporation.…”

mentioning

confidence: 99%

Cyclosporine Blocks Incorporation of HIV-1 Envelope Glycoprotein into Virions

Sokolskaja

Olivari²,

Zufferey

et al. 2010

J Virol

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Cyclosporine (CsA) decreases HIV-1 infectivity by blocking HIV-1 capsid (CA) interaction with target cell cyclophilin A (CypA). Yet, HIV-1 virions produced in the presence of CsA also exhibit decreased infectivity that was previously shown to be independent of the well-characterized HIV-1 CA-CypA interaction. Here, we demonstrate that CsA decreases gp120 and gp41 incorporation into HIV-1 virions and that the fusion of these virions with susceptible target cells is impaired. This effect was not observed with HIV-1 virions pseudotyped with the vesicular stomatitis virus glycoprotein or with the amphotropic envelope protein of murine leukemia virus. It was independent of calcineurin signaling, the endoplasmic reticulum luminal protein cyclophilin B, and the long cytoplasmic tail of gp41. Thus, cyclosporine blocks HIV-1 infectivity via two independent mechanisms, the first involving HIV-1 CA in target cells and the second involving HIV-1 Env in producer cells.

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Inhibition of HIV-1 Replication by Amphotericin B Methyl Ester

Cited by 60 publications

References 72 publications

Polyene antibiotic that inhibits membrane transport proteins

Polyene antibiotic that inhibits membrane transport proteins

Role of the Membrane-Spanning Domain of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein in Cell-Cell Fusion and Virus Infection

Cyclosporine Blocks Incorporation of HIV-1 Envelope Glycoprotein into Virions

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