A prediction based on the increase in thermal stability of the R403A substituted trimer-of-hairpins is that such substitutions should confer reduced sensitivity to LHR-mimetic peptide inhibitors. To test this view we compared the activity of the P BLV -391 antagonist of envelope fusion [17] against wild type or R403Asubstituted envelope. This peptide mimics residues Cys391 to Gln419 of BLV Env. In syncytium interference assays, P BLV -391 inhibited fusion catalysed by wild-type envelope with an IC 50 of 3.1760.09 mM (Fig. 4D ). However, P BLV -391 only inhibited fusion catalysed by R403A envelope with an IC 50 estimated to be .9 mM, and even at peptide concentrations up to 15 mM inhibition of syncytium formation was markedly damped indicating that both the potency and efficacy of the peptide was reduced against R403A substituted envelope (Fig. 4D) . Moreover, though more active against native envelope, a reciprocally substituted peptide antagonist, P BLV -R403A, failed to exhibit full potency against the R403 envelope derivative; P BLV -R403A inhibited wild-type envelope catalysed membrane fusion with an IC 50 of 1.360.1 mM, but inhibited the R403A envelope with an IC 50 of .6 mM (Fig. 4E) . In both experiments, C34 (a peptide mimetic of HIV-1 gp41 residues Gly627 to Leu661) was used as a negative control. Thus, improving the thermal stability of the trimer-of-hairpins form of a class-1 fusion protein significantly reduces the sensitivity of envelope to peptide inhibitors targeted to the coiled coil.