A Sphinganine Based Lipo-Peptide Impairs the Fusion Activity of the HIV gp41 Envelope Protein via a Multifaceted Mechanism

Sphingolipids and cholesterol form assemblies in the cell membrane termed ordered domains, many aspects of which were discovered via the study of viral entry and fusion [1]. These domains mediate HIV release from the cells and entry into them [2]. Alteration to either sphingolipid or cholesterol levels in these domains have been shown to block viral fusion. Infectivity can additionally be blocked by lipid conjugated peptides, termed lipo-peptides, which modulate various biological systems including viral fusion. These compounds have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu [3]. However, 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. Challenging this argument we investigated the antiviral mechanism of lipo-peptides comprised of an HIV envelope derived peptide and sphinganine, the lipid backbone of dihydrosphingomyelin enriched in the HIV membrane [4]. We uncovered a partnership that reduced CD4 diffusion and HIV-1 fusion peptide mediated lipid mixing. In addition, these lipo-peptides localized to the virus-cell and cell-cell contact sites. Moreover, the joint lipo-peptide disrupted HIV-1 fusion protein assembly and folding. Overall, the findings may be implicative to lipid-protein interactions in various biological systems.

1. Simons, K. and H. Garoff. J Gen Virol, 1980. 50.
2. Nguyen, D.H. and J.E. Hildreth. J Virol, 2000. 74.
3. Rajendran, L., et al. Science, 2008. 320.
4. Klug, Y.A., et al. Biochem J, 2014. 461.