title: Trimeric, coiled-coil extension on peptide fusion inhibitor of HIV-1 influences selection of resistance pathways.
abstract: Peptides corresponding to N- and C-terminal heptad repeat regions (HR1 and HR2, respectively) of viral fusion proteins can block infection of viruses in a dominant negative manner by interfering with refolding of the viral HR1 and HR2 to form a six-helix bundle (6HB) that drives fusion between viral and host cell membranes. The 6HB of the HIV gp41 (endogenous bundle) consists of an HR1 coiled-coil trimer with grooves lined by antiparallel HR2 helices. HR1 peptides form coiled-coil oligomers that may bind to gp41 HR2 as trimers to form a heterologous 6HB (inhibitor bundle) or to gp41 HR1 as monomers or dimers to form a heterologous coiled coil. To gain insights into mechanisms of Env entry and inhibition by HR1 peptides, we compared resistance to a peptide corresponding to 36 residues in gp41 HR1 (N36) and the same peptide with a coiled-coil trimerization domain fused to its N terminus (IZN36) that stabilizes the trimer and increases inhibitor potency (Eckert, D. M., and Kim, P. S. (2001) Proc. Nat. Acad. Sci. U.S.A. 98, 11187-11192). Whereas N36 selected two genetic pathways with equal probability, each defined by an early mutation in either HR1 or HR2, IZN36 preferentially selected the HR1 pathway. Both pathways conferred cross-resistance to both peptides. Each HR mutation enhanced the thermostability of the endogenous 6HB, potentially allowing the virus to simultaneously escape inhibitors targeting either gp41 HR1 or HR2. These findings inform inhibitor design and identify regions of plasticity in the highly conserved gp41 that modulate virus entry and escape from HR1 peptide inhibitors.
authors.affiliation: Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhuang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: De Feo
authors.forename: Russell
authors.initials: R
authors.lastname: Vassell
authors.forename: Carol D
authors.initials: CD
authors.lastname: Weiss
mesh_terms: D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000502:physiology*; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D017433:Protein Structure, Secondary; D053586:Virus Internalization
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1