Membrane interactions of the synthetic N-terminal peptide of HIV-1 gp41 and its structural analogs

Structural and functional studies assessed the membrane actions of the N te rminus of HIV-1 glycoprotein 41 000 (gp41). Earlier site-directed mutagenes is has shown that key amino acid changes in this gp41 domain inhibit viral infection and syncytia formation. Here, a synthetic peptide corresponding t o the N terminus of gp41 (FP; 23 residues, 519-541), and also FP analogs (F P520V/E with Val --> Glu at residue 520; FP527L/R with Leu --> Arg at 527, FP529F/Y with Phe --> Tyr at 529; and FPCLP1 with FP truncated at 525) inco rporating these modifications were prepared. When added to human erythrocyt es at physiologic pH, the lytic and aggregating activities of the FP analog s were much reduced over those with the wild-type FP, With resealed human e rythrocyte ghosts, the lipid-mixing activities of the FP analogs were also substantially depressed over that with the wild-type FP. Combined with resu lts from earlier studies, theoretical calculations using hydrophobic moment plot analysis and physical experiments using circular dichroism and Fourie r transform infrared spectroscopy indicate that the diminished lysis and fu sion noted for FP analogs may be due to altered peptide-membrane lipid inte ractions. These data confirm that the N-terminal gp41 domain plays critical roles in the cytolysis and fusion underlying HIV-cell infection. (C) 1999 Elsevier Science B.V. All rights reserved.