Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: DOI: 10.1017/S1462399402005434; 20 December 2002
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Role of lipid rafts in fusion of human immunodeficiency virus 1 (HIV-1) to CD4⁺ T cells

Jacques Fantini, Nicolas Garmy, Radhia Mahfoud and Nouara Yahi

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Figure 4. Role of lipid rafts in fusion of human immunodeficiency virus 1 (HIV-1) to CD4⁺ T cells. (a) Initial binding of HIV-1 to the host CD4⁺ T cell. CD4 is present in microdomains enriched in glycosphingolipids (GSLs) (e.g. GM3/Gb3) and cholesterol. The HIV-1 surface envelope glycoprotein gp120 binds to CD4, leaving its V3 domain available for secondary interactions with raft GSLs. At this stage, the HIV-1 transmembrane glycoprotein gp41 is still bound to gp120 in an inactive conformation. (b) Lateral assembly of the HIV-1 fusion complex. Once bound to CD4, the viral particle is conveyed to an appropriate co-receptor (e.g. chemokine receptors CXCR4 or CCR5 or other G-protein-coupled seven-transmembrane-domain receptors) by the GSL raft, which moves freely in the outer leaflet of the plasma membrane composed of other lipids such as glycerophospholipids (GPLs). (c) End of the binding phase. Following the primary interaction with CD4 in the raft environment, a conformational change in gp120 renders cryptic regions of the viral glycoprotein (including the V3 domain – shown as a hinged triangle) available for secondary interactions with an appropriate co-receptor. As seven-transmembrane domain receptors are almost flush with the cell membrane, binding of gp120 to the co-receptor moves the viral spike close to the target membrane. In addition, the raft begins to disperse, allowing close contact between the co-receptor and the CD4–gp120 complex. Additional conformational changes in the HIV-1 envelope glycoprotein trimer are necessary to unmask the fusion peptide at the N-terminus of the transmembrane glycoprotein gp41. These conformational changes are stimulated by GSLs, which act as lipid chaperones in the raft environment. (d) Beginning of the fusion reaction. The conformational change in gp120 is shown on the left; the conformational change in gp41, allowing the beginning of the fusion reaction, is shown on the right. Once the hydrophobic fusion peptide is ejected outside the viral spike, it faces a highly polar aqueous environment and consequently penetrates into the plasma membrane of the target cell, where it finds stabilising hydrophobic conditions. This irreversible process induces a close contact between the viral envelope and the plasma membrane, which fuse together, allowing the entry of the nucleocapsid in the cytoplasm of the target cell (fig004jfm).