Sphingolipids, cholesterol, and HIV-1: a paradigm in viral fusion.
Our previous studies show that the depletion of cholesterol or sphingolipids (raft-associated lipids) from receptor-bearing adherent cell lines blocks HIV-1 entry and HIV-1 Env-mediated membrane fusion. Here we have evaluated the mechanism(s) by which these lipids contribute to the HIV-1 Env-mediated membrane fusion. We report the following: (1) GSL depletion from a suspension T lymphocyte cell line (Sup-T1) reduced subsequent fusion with HIV-1IIIB-expressing cells by 70%. (2) Cholesterol depletion from NIH3T3 cells bearing HIV-1 receptors (NIH3T3CD4R5/NIH3T3CD4X4) did not impair subsequent fusion with HeLa cells expressing the corresponding HIV-1 Envs. In contrast GSL depletion from these targets reduced fusion by 50% suggesting that GSL facilitate fusion in different ways. (3) GSL-deficient GM95 cells bearing high receptors fused with HIV-1 Env-expressing cells at 37 degrees C with kinetics similar to that of GSL + NIH3T3 targets. Based on these observations, we propose that the plasma membrane cholesterol is required to maintain the integrity of receptor pools whereas GSLs are involved in stabilizing the coupling of inter-receptor pools.
Rawat
Satinder Singh
SS
Laboratory of Experimental and Computational Biology, Center for Cancer Research NCI-Frederick, NIH, P.O. Box B, Bldg. 469, Rm. 211, Miller Drive Frederick, MD, USA.
Viard
Mathias
M
Gallo
Stephen A
SA
Blumenthal
Robert
R
Puri
Anu
A
D016475:3T3 Cells / Q000821:virology; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D015728:Receptors, HIV / Q000187:drug effects / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism* / Q000494:pharmacology
C095823:1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; D015704:CD4 Antigens; D015686:Gene Products, env; D006028:Glycosphingolipids; D009025:Morpholines; D015728:Receptors, HIV; D013107:Sphingolipids; D002784:Cholesterol