title: In vivo patterns of resistance to the HIV attachment inhibitor BMS-488043.
abstract: Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4(+) lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC(50)] >10-fold greater than the baseline value) and four had high baseline EC(50)s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.
authors.affiliation: Virology, Bristol-Myers Squibb, Wallingford, CT 06492, USA.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Jie
authors.initials: J
authors.lastname: Fang
authors.forename: Hua
authors.initials: H
authors.lastname: Fang
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: Betsy
authors.initials: B
authors.lastname: Eggers
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Kadow
authors.forename: Dennis
authors.initials: D
authors.lastname: Grasela
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: Louis
authors.initials: L
authors.lastname: Alexander
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015704:CD4 Antigens / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007211:Indoles; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D019289:Pyruvic Acid; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D007211:Indoles; D010879:Piperazines; D019289:Pyruvic Acid; C509651:BMS-488043