title: In vitro selection and characterization of HIV-1 variants with increased resistance to sifuvirtide, a novel HIV-1 fusion inhibitor.
abstract: Sifuvirtide, a novel fusion inhibitor against human immunodeficiency virus type I (HIV-1), which is more potent than enfuvirtide (T20) in cell culture, is currently under clinical investigation for the treatment of HIV-1 infection. We now report that in vitro selection of HIV-1 variants resistant to sifuvirtide in the presence of increasing concentrations of sifuvirtide has led to several specific mutations in the gp41 region that had not been previously reported. Many of these substitutions were confined to the N-terminal heptad repeat region at positions 37, 38, 41, and 43, either singly or in combination. A downstream substitution at position 126 (N126K) in the C-terminal heptad repeat region was also found. Site-directed mutagenesis studies have further identified the critical amino acid substitutions and combinations thereof in conferring the resistant genotypes. Furthermore, the mutant viruses demonstrated variable degrees of cross-resistance to enfuvirtide, some of which are preferentially more resistant to sifuvirtide. Impaired infectivity was also found for many of the mutant viruses. Biophysical and structural analyses of the key substitutions have revealed several potential novel mechanisms against sifuvirtide. Our results may help to predict potential resistant patterns in vivo and facilitate the further clinical development and therapeutic utility of sifuvirtide.
authors.affiliation: AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Liu
authors.forename: Mei
authors.initials: M
authors.lastname: Shan
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
mesh_terms: D019943:Amino Acid Substitution; D003429:Cross Reactions; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D014644:Genetic Variation; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D000077560:Enfuvirtide; C505768:sifuvirtide