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Journal of Virology, July 2000, p. 6377-6385, Vol. 74, No. 14
0022-538X/00/$04.00+0

Glycosphingolipids Promote Entry of a Broad Range of Human Immunodeficiency Virus Type 1 Isolates into Cell Lines Expressing CD4, CXCR4, and/or CCR5

Peter Hug,1 Han-Ming Joseph Lin,1 Thomas Korte,1 Xiaodong Xiao,1 Dimiter S. Dimitrov,1 Ji Ming Wang,2 Anu Puri,1 and Robert Blumenthal1,*

Laboratory of Experimental and Computational Biology1 and Laboratory of Molecular Immunoregulation,2 Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702

Received 20 December 1999/Accepted 11 April 2000

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 Ca2+ 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.

* Corresponding author. Mailing address: Laboratory of Experimental and Computational Biology, Division of Basic Sciences, National Cancer Institute, Bld. 469, Rm. 213, National Institutes of Health, Frederick, MD 21702-1201. Phone: (301) 846-1446. Fax: (301) 846-6192. E-mail: blumen{at}helix.nih.gov.

Journal of Virology, July 2000, p. 6377-6385, Vol. 74, No. 14
0022-538X/00/$04.00+0


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