FUSION PEPTIDES DERIVED FROM THE HIV TYPE-1 GLYCOPROTEIN-41 ASSOCIATEWITHIN PHOSPHOLIPID-MEMBRANES AND INHIBIT CELL-CELL FUSION - STRUCTURE-FUNCTION STUDY

The fusion domain of human immunodeficiency virus (HIV-1) envelope gly coprotein (gp120-gp41) is a conserved hydrophobic region located at th e N terminus of the transmembrane glycoprotein (gp41). A V2E mutant ha s been shown to dominantly interfere with wild type envelope-mediated syncytium formation and virus infectivity. To understand this phenomen on, a 33-residue peptide (wild type, WT) identical to the N-terminal s egment of gp41 and its V2E mutant were synthesized, fluorescently labe led, and characterized, Both peptides inhibited HIV-1 envelope-mediate d cell cell fusion and had similar alpha-helical content in membrane m imetic environments, Studies with fluorescently labeled peptide analog ues revealed that both peptides have high affinity for phospholipid me mbranes, are susceptible to digestion by proteinase-K in their membran e-bound state, and tend to self- and coassemble in the membranes. In S DS-polyacrylamide gel electrophoresis the WT peptide formed dimers as well as higher order oligomers, whereas the V2E mutant only formed dim ers. The WT, but not the V2E mutant, induced liposome aggregation, des tabilization, and fusion. Moreover, the V2E mutant inhibited vesicle f usion induced by the WT peptide, probably by forming inactive heteroag gregates. These data form the basis for an explanation of the mechanis m by which the gp41 V2E mutant inhibits HIV-1 infectivity in cells whe n co expressed with WT gp41.