title: Selection with a peptide fusion inhibitor corresponding to the first heptad repeat of HIV-1 gp41 identifies two genetic pathways conferring cross-resistance to peptide fusion inhibitors corresponding to the first and second heptad repeats (HR1 and HR2) of gp41.
abstract: We generated four HIV-1 cultures that are resistant to a peptide fusion inhibitor corresponding to the first heptad repeat of gp41 in order to study mechanisms of resistance and gain insights into envelope glycoprotein-mediated membrane fusion. Two genetic pathways emerged that were defined by acquisition of a specific mutation in either the first or second heptad repeat region of gp41 (HR1 or the HR2, respectively). Each pathway was enriched in mutations that clustered in either HR2 and V3 or in HR1 and residues in or near CD4 contact sites. The gp41 mutations in both pathways not only accounted for resistance to the selecting HR1 peptide but also conferred cross-resistance to HR2 peptide fusion inhibitors and enhanced the stability of the six-helix bundle formed by the self-assembly of HR1 and HR2. The gp120 mutations alone enhanced fusion but did not appear to directly contribute to resistance. The implications of these findings for resistance mechanisms and regulation of envelope-mediated fusion are discussed.
authors: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, HFM-466, Bldg. 29, Room 532, 29 Lincoln Dr., Bethesda, MD 20892, USA.
authors: Wei
authors: W
authors: Wang
authors: Christopher J
authors: CJ
authors: De Feo
authors: Min
authors: M
authors: Zhuang
authors: Russell
authors: R
authors: Vassell
authors: Carol D
authors: CD
authors: Weiss
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D015700:HIV Envelope Protein gp41 / Q000235:genetics*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D012641:Selection, Genetic
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D050505:Mutant Proteins; C514787:gp41 protein, Human immunodeficiency virus 1