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 lipopeptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, binding to the membrane and thus elevating the local concentration of the peptide at the target site. In the present paper, we challenged this argument by exploring in-depth the antiviral mechanism of lipopeptides, which comprise sphinganine, the lipid backbone of DHSM (dihydrosphingomyelin), 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 lipopeptides to the virus-cell and cell-cell contact sites. Overall, the findings of the present study may suggest lipid-protein interactions in various biological systems and may help uncover a role for elevated DHSM in HIV-1 and its target cell membranes.
*Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
Yoel A
YA
Klug
*Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
Avraham
A
Ashkenazi
Mathias
M
Viard
§Flow Cytometry Unit, Department of Biological Services, Weizmann Institute of Science, Rehovot 7610001, Israel.
Ziv
Z
Porat
†Section on Membrane Structure and Function, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, U.S.A.
Robert
R
Blumenthal
*Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
Yechiel
Y
Shai
D015704:CD4 Antigens / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D017510:Protein Folding; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019076:Transgenes; D053586:Virus Internalization / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010455:Peptides; C514793:gp120 protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D008156:Luciferases; D013110:Sphingosine; C005682:safingol