Early and Late HIV-1 Membrane Fusion Events are Impaired by Sphinganine Lipidated Peptides that Target the Fusion Site

Lipid conjugated peptides have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu. These lipo-peptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, which is binding to the membrane, thus elevating the peptide’s local concentration at the target site. Here, we challenged this argument by exploring in-depth the antiviral mechanism of lipo-peptides, which are comprised of sphinganine, the lipid backbone of dihydrosphingomyelin (DHSM), and an HIV-1 envelope derived peptide. Surprisingly, we discovered a partnership between the lipid and the peptide that impaired early membrane fusion events by reducing CD4 receptor lateral diffusion and HIV-1 fusion peptide mediated lipid mixing. Moreover, only the joint function of sphinganine and its conjugate peptide disrupted HIV-1 fusion protein assembly and folding at the later fusion steps. Via imaging techniques we revealed for the first time the direct localization of these lipo-peptides to the virus-cell and cell-cell contact sites. Overall, the findings may be implicative to lipid-protein interactions in various biological systems and may help uncover DHSM’s role that is elevated in HIV-1 and its target cell membranes.

Source: BJ Cell - April 25, 2014 Category: Biochemistry Authors: Y Alexander Klug, A Ashkenazi, M Viard, Z Porat, R Blumenthal, Y Shai Tags: BJ Cell Source Type: research