[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Virology 08/2004; 78(14):7360-8. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inherent to their condition of obligate intracellular parasites, viruses rely on hijacking of cell host machinery for multiplication. This dependence on cellular factors also includes the use of cellular proteins and lipids for key steps of the viral life cycle, i.e. entry into the cell, genome replication, assembly, and release of progeny virus particles. Viruses can take advantage of cellular lipids as entry receptors, cofactors for membrane fusion, scaffolding molecules for replication complex assembly, and even as structural components of viral particles (especially in the case of enveloped viruses). Indeed, the relationship between viral infection and cellular lipids goes beyond a mere dependence on specific lipids for viral multiplication. Recent advances have uncovered a fine tuned intimate connection between lipid metabolism and viral infection. These studies have unveiled that viruses orchestrate profound alterations of cellular lipid metabolism that favour the accumulation of specific metabolites for their own purposes. For a wide variety of viruses this implies that infected cells undergo specific intracellular membrane rearrangements to build up virus-induced organelle-like structures that provide the adequate platforms for viral replication, which can also contribute to evasion of the innate immune response. Key roles of cellular lipids like cholesterol, fatty acids, or specific phospholipids have been related to these processes. To build up this specific microenvironment viruses co-opt cell host factors involved in membrane remodelling and lipid synthesis. The strong dependence of viral infection on specific lipids and cellular factors involved in their metabolism opens new lines of investigation for the search and development of alternative new antiviral strategies targeting lipid metabolism to interfere with virus multiplication.
[Show abstract][Hide abstract] ABSTRACT: HIV-1 uses CD4 and chemokine receptors to enter cells. However, other target membrane components may also be involved. This study examines the role of glycosphingolipids (GSL) in HIV-1 entry into primary lymphocytes and its modulation by an inhibitor of GSL biosynthesis.
CD4 lymphocytes purified from normal or the p-group subtype individuals that were defective in Gb3 synthesis were treated with a GSL biosynthesis inhibitor, 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP). The PPMP-treated cells were tested for HIV-1 replication by measuring p24 antigen production for 7-14 days post-infection and for susceptibility to HIV-1 Env-mediated fusion monitored by a fluorescent dye transfer assay. The effects of PPMP treatment on HIV-1 binding to CD4 lymphocytes were also examined by measuring HIV-1 p24.
CD4 lymphocytes from p donors that are devoid of Gb3, but have elevated levels of GM3 were highly susceptible to HIV-1 fusion/entry. Pre-treatment of primary human CD4 lymphocytes from normal or p-sub-group type with PPMP, significantly reduced HIV-1 replication with no change in CD4 and CXCR4 levels. Inhibition of HIV-1 infection was due to the block in HIV-1 Env-mediated plasma membrane fusion. Binding of HIV-1 to CD4 lymphocytes was not affected by PPMP treatment.
Manipulation of glycosphingolipid metabolic pathways may alter susceptibility of CD4 lymphocytes to HIV-1 entry.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.