Important note: Information in this article was accurate in July 2000. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, July 26, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- The AIDS virus boards a lipid raft that keeps it afloat as it searches for a way into a cell, a French research team suggests.
According to their hypothesis, the raft is made up of glycosphingolipid microdomains. Once it has bound to a CD4 cell receptor, HIV sails along the cell surface on the glycosphingolipid, dragging along the CD4 receptor like a dinghy until it finds an appropriate chemokine coreceptor. The coreceptor - CCR5 or CXC4R - then displaces the glycosphingolipid and begins the membrane-fusion process whereby the virus gains entry to the cell.
In a series of in vitro experiments, Djali Hammache of the St. Jerome Faculty of Sciences, Marseilles, France, and colleagues showed that the glycosphingolipids globotriaosylceramide (Gb3) and the ganglioside GM3 interact with the HIV gp120 envelope glycoprotein in the presence of CD4.
"These data suggest that glycosphingolipid microdomains are required in CD4-dependent fusion and that Gb3 and/or GM3 may function as alternative entry cofactors for selected HIV-1 isolates," they wrote.
Hammache et al. reported their findings in the Journal of Virology ("Human Erythrocyte Glycosphingolipids as Alternative Cofactors for Human Immunodeficiency Virus Type 1 (HIV-1) Entry: Evidence for CD4-Induced Interactions between HIV-1 gp120 and Reconstituted Membrane Microdomains of Glycosphingolipids (Gb3 and GM3)," J Virol, 1999;73(6):5244-8).
Glycosphingolipids are found with high frequency on human macrophages, and also are expressed by T cells including CD4(+) lymphocytes.
The researchers noted earlier studies showing that animal cells expressing CD4 can be infected with HIV if they are caused to express human erythrocyte glycosphingolipids (Puri, A.P. et al., Biochem Biophys Res Commun 1998 Jan 6;242(1):219-25. Moreover, Gb3 has been shown to be a functional fusion cofactor for HIV-1 with the X4 phenotype (Puri, A.P. et al., Proc Natl Acad Sci U S A 1998 Nov 24;95(24):14435-40). X4 HIV-1 uses the CXCR4 chemokine receptor as a coreceptor; the R5 phenotype uses the CCR5 chemokine receptor. Strains able to use either receptor are dubbed R5X4.
Hammache et al. explored interactions between Gb3, GM3, CD4, and gp120 from X4 and R5X4 strains of HIV-1.
"In the presence of CD4, Gb3 interacted preferentially with the X4 gp120, whereas GM3 interacted exclusively with the R5X4 gp120," they reported.
They proposed the raft metaphor, in which glycosphingolipids attach to both CD4 and gp120 to form a trimolecular complex.
"The role of the glycosphingolipid in this multimolecular organization could be to facilitate the migration of the CD4-gp120 complex to an appropriate receptor (e.g., CCR5 or CXCR4), since CD4 and these coreceptors are not physically associated in the absence of HIV-1," they proposed.
This work was supported by SIDACTION funds from the Fondation pour la Recherche Medicale.
The corresponding author for this study is Jacques Fantini, Laboratoire de Biochimie et Biologie de la Nutrition, ESA-CNRS 6033, Faculte des Sciences de St. Jerome, 13397 Marseille cedex 20, France. Phone: (33 491-288-761. Fax: 33 491-288-440. Email: <jacques.fantini@lbbn.u-3mrs.fr>.
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