(A) Schematic of gp160, the gp120 and gp41 subunits and a close-up of the gp41 ectodomain. Indicated are the positions and amino acid residues of peptide based fusion inhibitor T20. The GIV sequence in HR1 (position 36–38) of gp41 is underlined. (B) Proposed model for T20-dependent viral entry. Each box depicts one of three scenarios: T20-sensitive (GIV-SNY), T20-resistant (GIA-SNY) and T20-dependent (GIA-SKY). A simplified gp41 ectodomain comprised of only one subunit of HR1 (light grey cylinder) and HR2 (dark grey cylinder) joined by a loop region (black line) is used to depict a pre-fusion and post-fusion state of the peptide. The thickness of the arrows represents the speed of the conformational switch between pre- and post-fusion conformations. A white star represents the GIA mutation in HR1 and a black star represents the SKY mutation in HR2. Explanations for each reaction are provided on the right hand side.