Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Causes of cellular immunodeficiency frequently associated with cancer remain poorly understood. One possible mechanism is tumor cell membrane shedding of immunosuppressive molecules, such as the sialic acid-containing glycosphingolipids, gangliosides. To explore this interesting hypothesis and establish structure-activity relationships, we examined the effects of a series of highly purified human gangliosides on T cell function. In all, ten individual molecular species of two major biosynthetic pathways were compared for their ability to inhibit human T cell proliferative responses. They include GM1, GD1a, GD1b, and GT1b (the predominant normal brain species), and GM4, GM3, GM2, GD3, GD2 and GQ1b. Strikingly, each HPLC-purified molecule, from the simplest monosialoganglioside to the most complex polysialoganglioside, had potent inhibitory activity; even the ganglioside with the most elemental carbohydrate structure (GM4, one sialic acid linked to a monosaccharide) strongly inhibits T cell proliferative responses to tetanus toxoid (ID90 = 1.5 microM). The data also reveal a complex interplay between elements of oligosaccharide structure in determining immunosuppressive activity. Sialic acid is critical to maximal activity, and (i) immunosuppression is most potent in gangliosides containing a terminal sialic acid. (ii) Total desialylation almost abolishes activity and (iii) partial alteration (lactone formation) reduces activity. (iv) Activity is generally but not always higher with higher numbers of sialic acid residues/molecule, and (v) some larger neutral glycosphingolipids retain measurable immunosuppressive activity. Overall, the potent inhibition by gangliosides supports the hypothesis that shedding of these molecules by tumors creates a highly immunosuppressive microenvironment around the tumor, thereby inhibiting the function of infiltrating host leukocytes and contributing to diminished T cell responses in cancer.
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PMID:Immunosuppression by human gangliosides: I. Relationship of carbohydrate structure to the inhibition of T cell responses. 157 61

Glycolipid compositions of cells infected by human retroviruses (human immunodeficiency virus, HIV and/or human T-cell lymphotropic virus type I, HTLV-I) have been studied. Eight cell lines, comprising two HTLV-I-infected T-cell lines (MT-2 and MT-4), two HTLV-I-negative T-cell lines (Jurkat and MF), a macrophage cell line (U937), and three HIV-infected counterpart cell lines (MT-4/HIV, Jurkat/HIV and U937/HIV) were used. The neutral glycolipids and gangliosides isolated from these cell lines were compared. Among them, the HTLV-I-infected T-cell lines, MT-2 and MT-4, showed similar patterns for both neutral glycolipids and gangliosides. Neutral glycolipids (GlcCer and LacCer) of MT-2 and MT-4 cells were markedly decreased, and a ganglioside, GM3, of theirs was decreased to only a trace amount compared to that in other cell lines. Gangliosides of MT-4 and MT-4/HIV were further separated on an Iatrobeads column, and were identified as GM2, GM1a and GD1a by methylation and liquid secondary ion mass spectrometric analyses. Since the patterns of neutral glycolipids and gangliosides of MT-2 and MT-4 are unique, as compared to those of HTLV-I-negative cells, it is suggested that these changes are related to HTLV-1 infection. No prominent differences in the ganglioside compositions between HIV-infected and non-infected cell lines could be observed. But it is noteworthy that the contents of asialo-GM2 in Jurkat/HIV and MT-4/HIV cells were increased as compared to those in the parental cell lines.
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PMID:Glycosphingolipid compositions of human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus (HIV)-infected cell lines. 850 47

The membrane glycolipids galactosylceramide (GalCer) and sulfatide (SGalCer) have been reported to act as receptors of human immunodeficiency virus (HIV) on CD4- cell lines. We show here that these glycolipids are present on CD4+ cells purified from human blood and on in vitro-differentiated monocyte-derived macrophages (MDMs). We investigated the role they could play in HIV infection. Glycolipids of MDMs were characterized at the molecular level by immunolabeling and thin-layer chromatography immune overlay, using a panel of human-, rabbit-, or murine-specific antibodies. GalCer and SGalCer were expressed at the surface of MDMs as assessed by indirect immunofluorescence and flow cytometry analysis, and they could be characterized with specific antibodies in the cellular glycolipid extracts in addition to GM1, GM3, and GD1b gangliosides. Recombinant 125-I-labeled gp160 specifically bound to GalCer, SGalCer, GM1, and GM3 as well as to phospholipids (phosphatidylethanolamine and phosphatidylserine) from MDM extracts. Anti-SGalCer monoclonal antibodies (MAbs), but not anti-GalCer antibodies, entailed limited (30-40%) but significant inhibition of gp160 binding to MDMs. However, the four human anti-SGalCer MAbs and the three murine or rabbit ant-GalCer antibodies tested did not inhibit HIV infection of MDMs, in contrast to CD4 antibody anti-Leu3a tested in parallel. These findings suggests that although HIV envelope glycoprotein can bind to SGalCer and GalCer from CD4+ MDM extracts, these glycolipids do not apparently act as HIV coreceptors nor are they involved in HIV infection of these cells.
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PMID:Membrane glycolipids and human immunodeficiency virus infection of primary macrophages. 874 80

Synthetic multibranched peptides derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120 inhibit HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms: competitive inhibition of HIV-1 binding to CD4-/GalCer+ colon cells and postbinding inhibition of HIV-1 fusion with CD4+ lymphocytes. In the present study, we have characterized the cellular binding sites for the V3 peptide SPC3, which possesses eight V3 consensus motifs GPGRAF radially branched on a neutral polyLys core matrix. These binding sites are glycosphingolipids that share a common structural determinant, i.e., a terminal galactose residue with a free hydroxyl group in position 4: GalCer/sulfatide on CD4-/GalCer+ colon cells; LacCer and its sialosyl derivatives GM3 and GD3 on CD4+ human lymphocytes. These data suggest that the V3 peptide binds to the GalCer/sulfatide receptor for HIV-1 gp120 on HT-29 cells and thus acts as a competitive inhibitor of virus binding to these CD4- cells, in full agreement with previously published virological data. In contrast, SPC3 does not bind to the CD4 receptor, in agreement with the data showing that the peptide inhibits HIV-1 infection of CD4+ cells by acting at a postattachment step. The binding of SPC3 to LacCer, GM3, and GD3, expressed by CD4+ lymphocytes, suggests a role for these glycosphingolipids in the fusion process between the viral envelope and the plasma membrane of CD4+ cells. Since the multivalent peptide can theoretically bind to several of these glycosphingolipids, we hypothesize that the resulting cross-linking of membrane components may affect the fluidity of the plasma membrane and/or membrane curvature, altering the virus-cell fusion mechanism.
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PMID:SPC3, a V3 loop-derived synthetic peptide inhibitor of HIV-1 infection, binds to cell surface glycosphingolipids. 896 29

Cellular glycosphingolipids mediate the fusion between some viruses and the plasma membrane of target cells. In the present study, we have analyzed the interaction of human immunodeficiency virus (HIV)-1 and HIV-2 surface envelope glycoproteins from distinct viral isolates with monolayers of various glycosphingolipids at the air-water interface. The penetration of the viral glycoproteins into glycosphingolipid monolayers was detected as an increase in the surface pressure. We found that HIV-1 recombinant gp120 (IIIB isolate) could penetrate into a monomolecular film of alpha-hydroxylated galactosylceramide (GalCer-HFA), while ceramides, GluCer, and nonhydroxylated GalCer were totally inactive. The glycoproteins isolated from HIV-1 isolates LAI and NDK and from HIV-2(ROD) could also interact with a GalCer-HFA monolayer, whereas gp120 from HIV-1(SEN) and HIV-1(89.6) did not react. These data correlated with the ability of the corresponding viruses to gain entry into the CD4(-)/GalCer+ cell line HT-29, demonstrating the determinant role of GalCer-HFA in this CD4-independent pathway of HIV-1 and HIV-2 infection. In contrast, all HIV-1 and HIV-2 glycoproteins tested were found to interact with a monolayer of GM3, a ganglioside abundantly expressed in the plasma membrane of CD4(+) lymphocytes and macrophages. A V3 loop-derived synthetic peptide inhibitor of HIV-1 and HIV-2 infection in both CD4(-) and CD4(+) cells could penetrate into various glycosphingolipid monolayers, including GalCer-HFA and GM3. Taken together, these data suggest that the adsorption of human immunodeficiency viruses to the surface of target cells involves an interaction between the V3 domain of the surface envelope glycoprotein and specific glycosphingolipids, i.e. GalCer-HFA for CD4(-) cells and GM3 for CD4(+) cells.
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PMID:Specific interaction of HIV-1 and HIV-2 surface envelope glycoproteins with monolayers of galactosylceramide and ganglioside GM3. 952 94

Glycosphingolipids from human erythrocytes mediate CD4-dependent fusion with cells expressing human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins. To identify the glycosphingolipid(s) which participates in the fusion process, we have analyzed the interaction of HIV-1 gp120 (X4 and R5X4 isolates) with reconstituted membrane microdomains of human erythrocyte glycosphingolipids. We identified globotriaosylceramide (Gb3) and ganglioside GM3 as the main glycosphingolipids recognized by gp120. In the presence of CD4, Gb3 interacted preferentially with the X4 gp120, whereas GM3 interacted exclusively with the R5X4 gp120. These data suggest that glycosphingolipid microdomains are required in CD4-dependent fusion and that Gb3 and/or GM3 may function as alternative entry cofactors for selected HIV-1 isolates.
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PMID:Human erythrocyte glycosphingolipids as alternative cofactors for human immunodeficiency virus type 1 (HIV-1) entry: evidence for CD4-induced interactions between HIV-1 gp120 and reconstituted membrane microdomains of glycosphingolipids (Gb3 and GM3). 1023 96

Treatment of human osteosarcoma cells, expressing CD4 and various chemokine receptors, with the glucosylceramide synthase inhibitor 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), blocked target membrane glycosphingolipid (GSL) biosynthesis and reduced the susceptibility of cells to infection and fusion mediated by envelope glycoproteins from a variety of human immunodeficiency virus type 1 (HIV-1) isolates that utilize CXCR4 and/or CCR5. PPMP treatment of the cell lines did not significantly change the cell surface expression of CD4, CXCR4, and/or CCR5, nor did it alter the chemokine receptor association with CD4. PPMP-treated cells exhibited no changes in chemokine-induced Ca(2+) mobilization and chemotaxis. However, massive envelope glycoprotein conformational changes triggered by CD4 and the appropriate chemokine receptor on the target membrane were inhibited when the target cells were treated with PPMP. Addition of various purified GSLs to PPMP-treated target cells showed that for all isolates tested, globotriaosylceramide (Gb3) was the most potent GSL in restoring the fusion susceptibility of target cells with cells expressing HIV-1 envelope glycoproteins; addition of the monosialoganglioside GM3 yielded a slight enhancement of fusion susceptibility. Our data are consistent with the notion that a limited number of specific GSL species serve as crucial elements in organizing gp120-gp41, CD4, and an appropriate chemokine receptor into a membrane fusion complex.
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PMID:Glycosphingolipids promote entry of a broad range of human immunodeficiency virus type 1 isolates into cell lines expressing CD4, CXCR4, and/or CCR5. 1086 48

The V3-loop region in the envelope protein gp120 of HIV is critical for viral infection, but its interaction with the target cells is not clear. Using synthetic peptides, representing linear V3 sequences as reagents, we obtained evidence to show inhibition of infection by both T-cell- and macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1) (X4 and R5, respectively), without interfering with gp120-CD4 interaction, by the V3 peptides through binding to host cell membrane glycosphingolipids (GSL). Synthetic peptides mimicking the central 15-21 amino acid sequence of the V3-loop region in both X4 and R5 strains of HIV-1 competed with and blocked the entry of both types of HIV isolates. These HIV-inhibitory V3 peptides exhibited specific binding to target cells that was not competed by antibodies to either the primary receptor CD4 or the co-receptors CXCR-4 and CCR5. However, R15K, the V3 peptide from HIV-1 IIIB gp120 exhibited specific binding to three distinct cell surface GSL: GM3, Gb3, and GalCer. Further, R15K inhibited GSL binding of gp120 from both HIV-1 IIIB (X4, Gb3-binding strain) and HIV-1 89.6 (X4R5, GM3-binding strain). Together, these results suggest a critical V3-mediated post-CD4-binding event involving cell surface GSL binding represented by the HIV-inhibitory V3 peptides, that is common for the entry of diverse HIV-1 strains and may be targeted for the development of novel HIV therapeutics aimed at blocking viral entry.
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PMID:A post-CD4-binding step involving interaction of the V3 region of viral gp120 with host cell surface glycosphingolipids is common to entry and infection by diverse HIV-1 strains. 1240 7

GM3, a major ganglioside of T lymphocytes, promotes human immunodeficiency virus type 1 (HIV-1) entry via interactions with HIV-1 receptors and the viral envelope glycoprotein (Env). Increased GM3 levels in T lymphocytes and the appearance of anti-GM3 antibodies in AIDS patients have been reported earlier. In this study, we investigated the effect of GM3 regulation on HIV-1 entry by utilizing a mouse cell line (B16F10), which expresses exceptionally high levels of GM3. Strikingly, B16 cells bearing CD4, CXCR4, and/or CCR5 were highly resistant to CD4-dependent HIV-1 Env-mediated membrane fusion. In contrast, these targets supported membrane fusion mediated by CD4-requiring HIV-2, SIV, and CD4-independent HIV-1 Envs. Coreceptor function was not impaired by GM3 overexpression as indicated by Ca(2+) fluxes mediated by the CXCR4 ligand SDF-1alpha and the CCR5 ligand MIP-1beta. Reduction in GM3 levels of B16 target cells resulted in a significant recovery of CD4-dependent HIV-1 Env-mediated fusion. We propose that GM3 in the plasma membrane blocks HIV-1 Env-mediated fusion by interfering with the lateral association of HIV-1 receptors. Our findings offer a novel mechanism of interplay between membrane lipids and receptors by which host cells may escape viral infections.
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PMID:Elevated expression of GM3 in receptor-bearing targets confers resistance to human immunodeficiency virus type 1 fusion. 1522 Apr 9

Retroviruses acquire a lipid envelope during budding from the membrane of their hosts. Therefore, the composition of this envelope can provide important information about the budding process and its location. Here, we present mass spectrometry analysis of the lipid content of human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MLV). The results of this comprehensive survey found that the overall lipid content of these viruses mostly matched that of the plasma membrane, which was considerably different from the total lipid content of the cells. However, several lipids are enriched in comparison to the composition of the plasma membrane: (i) cholesterol, ceramide, and GM3; and (ii) phosphoinositides, phosphorylated derivatives of phosphatidylinositol. Interestingly, microvesicles, which are similar in size to viruses and are also released from the cell periphery, lack phosphoinositides, suggesting a different budding mechanism/location for these particles than for retroviruses. One phosphoinositide, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], has been implicated in membrane binding by HIV Gag. Consistent with this observation, we found that PI(4,5)P(2) was enriched in HIV-1 and that depleting this molecule in cells reduced HIV-1 budding. Analysis of mutant virions mapped the enrichment of PI(4,5)P(2) to the matrix domain of HIV Gag. Overall, these results suggest that HIV-1 and other retroviruses bud from cholesterol-rich regions of the plasma membrane and exploit matrix/PI(4,5)P(2) interactions for particle release from cells.
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PMID:Retroviruses human immunodeficiency virus and murine leukemia virus are enriched in phosphoinositides. 1879 74


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