LIPID-MEMBRANE FUSION INDUCED BY THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GP41 N-TERMINAL EXTREMITY IS DETERMINED BY ITS ORIENTATION IN THE LIPID BILAYER

The amino-terminal extremity of the human immunodeficiency virus type 1 transmembrane protein (gp41) is thought to play a pivotal role in th e fusion of virus membranes with the plasma membrane of the target cel l and in syncytium formation, Peptides with sequences taken from the h uman immunodeficiency virus type 1 gp41 fusogenic (synthetic peptides SPwt and SP-2) and nonfusogenic (SP-3 and SP-4) glycoproteins adopt ma inly a beta-sheet conformation in the absence of lipid, as determined by attenuated total reflection Fourier transform infrared spectroscopy , and after interaction with large unilamellar liposomes, the beta-she et is partly converted into an alpha-helical conformation, Peptides SP wt and SP-2 but not SP-3 or SP-4 were able to promote lipid mixing as assessed by fluorescence energy transfer assay and dye leakage in a ve sicle leakage assay, By using polarized attenuated total reflection Fo urier transform infrared spectroscopy, SPwt and SP-2 were found to ado pt an oblique orientation in the lipid membrane whereas SP-3 and SP-4 were oriented nearly parallel to the plane of the membrane. These find ings confirm the correlation between the membrane orientation of the a lpha-helix and the lipid mixing ability in vitro. Interestingly, the d ata provide a direct correlation with the fusogenic activity of the pa rent glycoproteins in vivo.