Elevated expression of GM3 in receptor-bearing targets confers resistance to human immunodeficiency virus type 1 fusion.
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.
Rawat
Satinder S
SS
Laboratory of Experimental and Computational Biology, Center for Cancer Research NCI-Frederick, NIH, Frederick, MD 21702-1201, USA.
Gallo
Stephen A
SA
Eaton
Julie
J
Martin
Thomas D
TD
Ablan
Sherimay
S
KewalRamani
Vineet N
VN
Wang
Ji Ming
JM
Blumenthal
Robert
R
Puri
Anu
A
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D005679:G(M3) Ganglioside / Q000378:metabolism* / Q000494:pharmacology; D015686:Gene Products, env / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity*; D015498:HIV-2 / Q000472:pathogenicity; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects*; D051379:Mice; D041681:NIH 3T3 Cells; D015728:Receptors, HIV / Q000737:chemistry / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity
D015704:CD4 Antigens; D005679:G(M3) Ganglioside; D015686:Gene Products, env; D015728:Receptors, HIV