Role of glycosphingolipid microdomains in CD4-dependent HIV-1 fusion

The fusion of HIV-1 with the plasma membrane of CD4(+) cells is triggered b y the interaction of HIV-1 surface envelope glycoprotein gp120 with the CD4 receptor, and requires coreceptors (CCR5 and CXCR4). Recent advances in th e study of HIV-1 entry into CD4(+) cells suggest that glycosphingolipids (G SL) may also participate in the fusion process. GSL are organized In functi onal microdomains which are associated with specific membrane proteins such as CD4. GSL-enriched microdomains were purified from human lymphocytes and reconstituted as a monomolecular film at the air-water interface of a Lang muir film balance. Surface pressure measurements allowed to characterize th e sequential interaction of GSL with CD4 and with gp120, Using this approac h, we identified globotriaosylceramide (Gb3) and ganglioside GM3 as the mai n lymphocyte GSL recognized by gp120. In both cases, the interaction was sa turable and dramatically increased by CD4, We propose that GSL microdomains behave as moving platforms allowing the recruitment of HIV-1 coreceptors a fter the initial interaction between the viral particle and CD4. According to this model, the GSL microdomain may : i) stabilize the attachment of the virus with the cell surface th rough multiple low affinity interactions be tween the V3 domain of gp120 and the carbohydrate moiety of GSL, and ii) co nvey the virus to an appropriate coreceptor by moving freely in the outer l eaflet of the plasma membrane. This model can be extrapolated to all envelo pe viruses (e.g. influenza virus) that use cell surface GSL of the host cel ls as receptors or coreceptors.