Effect of HR1 and HR2 Mutations on Drug-Resistance.

<p>The role of individual gp41 mutations on drug-resistance was determined using site-directed mutagenesis of the pNBaL vector. The gp41 mutations identified in RC-101 resistant virus, Q66R and Q66R+N126K, were used to understand contributions to drug resistance. We also tested mutations shown to confer resistance to ENF, V38A and V38A+N126K. Equal concentrations of infectious virus, as determined by TCID50, were used to inoculate TZM-bl cells with increasing concentrations of RC-101 and ENF. Error bars represent SEM. Percent inhibition was calculated from RLU values and normalized to vehicle control (<b>A</b>) (N = 3−5). The structure PDB 1IF3 was used to model the positions of primary gp41 mutations. HR1 (blue) mutations Q66R (<b>B</b>) and V38A (<b>C</b>) are shown along with nearby residues on HR2 (green) of the same gp41 molecule. Two additional gp41 molecules making up the 6-helix bundle are shown in gray.