Heptad-repeat-2 mutations enhance the stability of the enfuvirtide-resistant HIV-1 gp41 hairpin structure.
Enfuvirtide (T20) is a peptide-based fusion inhibitor derived from the heptad repeat 2 (HR2) region of HIV-1 glycoprotein 41 (gp41). The inhibitor binds to the gp41 heptad repeat 1 (HR1) region, thereby blocking viral HR1/HR2 association. Mutations in HR1 have been reported to cause enfuvirtide resistance and reduce viral fitness. In this study, we first showed that scores obtained by a residue-specific all-atom probability discriminatory function (RAPDF) may be used as a reliable predictor of structural stability of gp41 mutants by comparing it to experimentally determined melting temperatures, and as a reliable indicator of enfuvirtide resistance by comparing it to experimentally determined fusion inhibition and viral fitness levels. We then generated an initial set of 28 theoretical structures of the HR1/HR2 hairpin complex where each structure consists of one mutation on HR1 known to cause enfuvirtide resistance and a wild-type amino acid at the corresponding HR2 residue. Mutations were then introduced in the corresponding HR2 residue of each structure where the wild-type amino acid was changed to each of the other nineteen amino acids. The enfuvirtide-resistant HR1 mutants with compensatory mutations at the corresponding HR2 residues had better RAPDF scores than those HR1 mutants with wild-type HR2. This indicates that mutations in HR2 improve structural stability of the HR1/HR2 hairpin complex and may lead to enhanced enfuvirtide resistance when present with resistant HR1 mutations. Modification of the amino acid side chains that contribute to enfuvirtide resistance using the RAPDF scores as a guide may help design of a second generation of fusion inhibitors against the enfuvirtide-resistant strains.
Jenwitheesuk
Ekachai
E
Department of Microbiology, University of Washington, School of Medicine, Seattle, WA 98195, USA.
Samudrala
Ram
R
D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics* / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008956:Models, Chemical; D009154:Mutation; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide