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Journal of Virology, July 2004, p. 7360-7368, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7360-7368.2004

Elevated Expression of GM3 in Receptor-Bearing Targets Confers Resistance to Human Immunodeficiency Virus Type 1 Fusion

Satinder S. Rawat,¹ Stephen A. Gallo,¹ Julie Eaton,¹ Thomas D. Martin,² Sherimay Ablan,^1, Vineet N. KewalRamani,² Ji Ming Wang,³ Robert Blumenthal,¹ and Anu Puri^1*

Laboratory of Experimental and Computational Biology,¹ HIV-Drug Resistance Program,² Laboratory of Molecular Immunoregulation, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702³

Received 28 January 2004/ Accepted 1 March 2004

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 Ca²⁺ fluxes mediated by the CXCR4 ligand SDF-1 and the CCR5 ligand MIP-1ß. 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.

Present address: HIV-Drug Resistance Program, NCI-Frederick, NIH, Frederick, MD 21702.

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