A novel soluble mimic of the glycolipid, globotriaosyl ceramide inhibits HIV infection

Lund, Nicole; Branch, Donald R.; Mylvaganam, Murugespillai; Chark, Davin; Ma, Xiongfeng; Sakac, Darinka; Binnington, Beth; Fantini, Jacques; Puri, Anu; Blumenthal, Robert; Lingwood, Clifford A.

doi:10.1097/01.aids.0000206499.78664.58

Cited by 62 publications

(66 citation statements)

References 49 publications

(57 reference statements)

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“…Like VT, gp120/GSL binding is modulated by the lipid moiety (37). Cholesterol is important in HIV infection (38,39), and Gb 3 , and Gb 3 analogues, are HIV inhibitors (40,41).…”

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confidence: 99%

A Major Fraction of Glycosphingolipids in Model and Cellular Cholesterol-containing Membranes Is Undetectable by Their Binding Proteins

Mahfoud

Manis

Binnington

et al. 2010

Journal of Biological Chemistry

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Glycosphingolipids (GSLs) accumulate in cholesterol-enriched cell membrane domains and provide receptors for protein ligands. Lipid-based "aglycone" interactions can influence GSL carbohydrate epitope presentation. To evaluate this relationship, Verotoxin binding its receptor GSL, globotriaosyl ceramide (Gb 3 ), was analyzed in simple GSL/cholesterol, detergent-resistant membrane vesicles by equilibrium density gradient centrifugation. Vesicles separated into two Gb 3/ cholesterolcontaining populations. The lighter, minor fraction (<5% total GSL), bound VT1, VT2, IgG/IgM mAb anti-Gb 3 , HIVgp120 or Bandeiraea simplicifolia lectin. Only IgM anti-Gb 3 , more tolerant of carbohydrate modification, bound both vesicle fractions. Post-embedding cryo-immuno-EM confirmed these results. This appears to be a general GSL-cholesterol property, because similar receptor-inactive vesicles were separated for other GSLprotein ligand systems; cholera toxin (CTx)-GM1, HIVgp120-galactosyl ceramide/sulfatide. Inclusion of galactosyl or glucosyl ceramide (GalCer and GlcCer) rendered VT1-unreactive Gb 3 /cholesterol vesicles, VT1-reactive. We found GalCer and GlcCer bind Gb 3 , suggesting GSL-GSL interaction can counter cholesterol masking of Gb 3 . The similar separation of Vero cell membrane-derived vesicles into minor "binding," and major "non-binding" fractions when probed with VT1, CTx, or anti-SSEA4 (a human GSL stem cell marker), demonstrates potential physiological relevance. Cell membrane GSL masking was cholesterol-and actin-dependent. Cholesterol depletion of Vero and HeLa cells enabled differential VT1B subunit labeling of "available" and "cholesterol-masked" plasma membrane Gb 3 pools by fluorescence microscopy. Thus, the model GSL/cholesterol vesicle studies predicted two distinct membrane GSL formats, which were demonstrated within the plasma membrane of cultured cells. Cholesterol masking of most cell membrane GSLs may impinge many GSL receptor functions.

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“…Like VT, gp120/GSL binding is modulated by the lipid moiety (37). Cholesterol is important in HIV infection (38,39), and Gb 3 , and Gb 3 analogues, are HIV inhibitors (40,41).…”

mentioning

confidence: 99%

A Major Fraction of Glycosphingolipids in Model and Cellular Cholesterol-containing Membranes Is Undetectable by Their Binding Proteins

Mahfoud

Manis

Binnington

et al. 2010

Journal of Biological Chemistry

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“…Adamantyl Gb 3, a soluble mimic of globotriaosyl ceramide, Gb 3 (35), preferentially partitions into aqueous phase, as opposed to organic solvents, which completely sequester Gb 3 . Unlike the water-soluble, lipid-free Gb 3 oligosaccharide, adaGb 3 retains high affinity verotoxin (VT) binding in aqueous solution (35) and indeed shares some properties of Gb 3 -cholesterol complexes in solution (36), which may relate to its several bioactivities (37,38). Exchange of the GSL fatty acid moiety for adamantane also proved effective to generate a water-soluble, ligand-binding, bioactive mimic of sulfogalactosyl ceramide (sulfatide) (39 -41), suggesting that this could represent a general method for the generation of soluble bioactive GSL mimics.…”

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confidence: 99%

Adamantyl Glycosphingolipids Provide a New Approach to the Selective Regulation of Cellular Glycosphingolipid Metabolism

Kamani

Mylvaganam

Tian

et al. 2011

Journal of Biological Chemistry

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Mammalian glycosphingolipid (GSL) precursor monohexosylceramides are either glucosyl-or galactosylceramide (GlcCer or GalCer). Most GSLs derive from GlcCer. Substitution of the GSL fatty acid with adamantane generates amphipathic mimics of increased water solubility, retaining receptor function. We have synthesized adamantyl GlcCer (adaGlcCer) and adamantyl GalCer (adaGalCer). AdaGlcCer and adaGalCer partition into cells to alter GSL metabolism. At low dose, adaGlcCer increased cellular GSLs by inhibition of glucocerebrosidase (GCC). Recombinant GCC was inhibited at pH 7 but not pH 5. In contrast, adaGalCer stimulated GCC at pH 5 but not pH 7 and, like adaGlcCer, corrected N370S mutant GCC traffic from the endoplasmic reticulum to lysosomes. AdaGalCer reduced GlcCer levels in normal and lysosomal storage disease (LSD) cells. At 40 M adaGlcCer, lactosylceramide (LacCer) synthase inhibition depleted LacCer (and more complex GSLs), such that only GlcCer remained. In Vero cell microsomes, 40 M adaGlcCer was converted to adaLacCer, and LacCer synthesis was inhibited. AdaGlcCer is the first cell LacCer synthase inhibitor. At 40 M adaGalCer, cell synthesis of only Gb 3 and Gb 4 was significantly reduced, and a novel product, adamantyl digalactosylceramide (adaGb 2 ), was generated, indicating substrate competition for Gb 3 synthase. AdaGalCer also inhibited cell sulfatide synthesis. Microsomal Gb 3 synthesis was inhibited by adaGalCer. Metabolic labeling of Gb 3 in Fabry LSD cells was selectively reduced by adaGalCer, and adaGb 2 was produced. AdaGb 2 in cells was 10-fold more effectively shed into the medium than the more polar Gb 3 , providing an easily eliminated "safety valve" alternative to Gb 3 accumulation. Adamantyl monohexosyl ceramides thus provide new tools to selectively manipulate normal cellular GSL metabolism and reduce GSL accumulation in cells from LSD patients.

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“…It has been suggested that GM3 is bound only by gp120 from R5 strains whereas Gb3 is bound by both X4 and R5 strains (Hammache et al, 1999). GSL analogues have been shown to inhibit HIV infection (Fantini et al, 1997, Faroux-Corlay et al, 2001, Garg et al, 2008, Lund et al, 2006, Weber et al, 2000and the efficacy of such analogues depends on the nature of both the carbohydrate and lipid moieties. In addition, GalCer binds to gp120 associated gp41 (Alfsen & Bomsel, 2002), the fusion heptad repeat C-terminal peptide of which, mediates viral/host membrane fusion (Shnaper et al, 2004).…”

Section: Gsl Receptorsmentioning

confidence: 99%

“…In collaboration with Blumenthal's group at NIH we have found that adaGb 3 is also able to inhibit gp120/CD4/chemokine coreceptor dependent host cell fusion irrespective of gp120 type (R5 or X4 tropic, HIV-1 or HIV-2) as monitored in an indicator system in which gp120 is transfected into one indicator cell and the chemokine receptor into another (Lund et al, 2006).…”

Section: Adagb 3 Inhibits Hiv Infectionmentioning

confidence: 99%

“…Studies have indicated that oral administration of DGJ to transgenic mice expressing a human mutant -Gal A substantially elevated enzyme activity in major organs (Fan et al, 1999). Because Gb 3 has now been suggested by the studies of Lund et al (Lund et al, 2006). as an important component for prevention of the HIV entry mechanism, the use of DGJ to pharmacologically increase Gb 3 expression may be useful for HIV prevention strategies.…”

Section: Pharmacologic Modulation Of Gb 3 Expressionmentioning

confidence: 99%

See 1 more Smart Citation

Glycosphingolipids in HIV/AIDS: The Potential Therapeutic Application

Lingwood¹,

Branch²

2011

Understanding HIV/AIDS Management and Care - Pandemic Approaches in the 21st Century

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A novel soluble mimic of the glycolipid, globotriaosyl ceramide inhibits HIV infection

Abstract: These results suggest that adamantylGb3 may provide a new basis for blocking HIV infections, irrespective of HIV envelope/chemokine co-receptor preference or resistance to other therapeutics.

Cited by 62 publications

References 49 publications

A Major Fraction of Glycosphingolipids in Model and Cellular Cholesterol-containing Membranes Is Undetectable by Their Binding Proteins

A Major Fraction of Glycosphingolipids in Model and Cellular Cholesterol-containing Membranes Is Undetectable by Their Binding Proteins

Adamantyl Glycosphingolipids Provide a New Approach to the Selective Regulation of Cellular Glycosphingolipid Metabolism

Glycosphingolipids in HIV/AIDS: The Potential Therapeutic Application

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