AN AMPHIPATHIC PEPTIDE FROM THE C-TERMINAL REGION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS ENVELOPE GLYCOPROTEIN CAUSES PORE FORMATION IN MEMBRANES

The peptide fragment of the carboxy-terminal region of the human immun odeficiency virus (HIV) transmembrane protein (gp41) has been implicat ed in T-cell death. This positively charged, amphipathic helix (amino acids 828 to 848) of the envelope protein is located within virions or cytoplasm. We studied the interaction of the isolated, synthetic amph ipathic helix of gp41 with planar phospholipid bilayer membranes and w ith Sf9 cells using voltage clamp, potentiodynamic, and single-cell re cording techniques. We found that the peptide binds strongly to planar membranes, especially to the negatively charged phosphatidylserine bi layer. In the presence of micromolar concentrations of peptide suffici ent to make its surface densities comparable,vith those of envelope gl ycoprotein molecules in HIV virions, an increase in bilayer conductanc e and a decrease in bilayer stability were observed, showing pore form ation in the planar lipid bilayers. These pores were permeable to both monovalent and divalent cations, as well as to chloride. The exposure of the inner leaflet of cell membranes to even 25 nM peptide increase d membrane conductance. We suggest that the carboxy terminal fragment of the HIV type 1 envelope protein may interact,vith the cell membrane of infected T cells to create lipidic pores which increase membrane p ermeability, leading to sodium and calcium flux into cells, osmotic sw elling, and T-cell necrosis or apoptosis.