Mode of action of an antiviral peptide from HIV-1 - Inhibition at a post-lipid mixing stage

DP178, a synthetic peptide corresponding to a segment of the transmembrane envelope glycoprotein (gp41) of human immunodeficiency virus, type 1 (HIV-l ), is a potent inhibitor of viral infection and virus-mediated cell-cell fu sion, Nevertheless, DP178 does not contain gp41 coiled-coil cavity binding residues postulated to be essential for inhibiting HIV-1 entry. We find tha t DP178 inhibits phospholipid redistribution mediated by the HIV-1 envelope glycoprotein at a concentration 8 times greater than that of solute redist ribution (the IC,, values are 43 and 335 nM, respectively), In contrast, C3 4, a synthetic peptide which overlaps with DP178 but contains the cavity bi nding residues, did not show this phenomenon (11 and 25 nM, respectively). The ability of DP178 to inhibit membrane fusion at a post-lipid mixing stag e correlates with its ability to bind and oligomerize on the surface of mem branes. Furthermore, our results are consistent with a model in which DP178 inhibits the formation of gp41 viral hairpin structure at low affinity, wh ereas C34 inhibits its formation at high affinity: the failure to form the viral hairpin prevents both lipid and solute from redistributing between ce lls, However, our data also suggest an additional membrane-bound inhibitory site for DP178 in the ectodomain of gp41 within a region immediately adjac ent to the membrane-spanning domain. By binding to this higher affinity sit e, DP178 inhibits the recruitment of several. gp41-membrane complexes, thus inhibiting fusion pore formation.