title: Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody ibalizumab.
abstract: Ibalizumab (formerly TNX-355) is a first-in-class, monoclonal antibody inhibitor of CD4-mediated human immunodeficiency type 1 (HIV-1) entry. Multiple clinical trials with HIV-infected patients have demonstrated the antiviral activity, safety, and tolerability of ibalizumab treatment. A 9-week phase Ib study adding ibalizumab monotherapy to failing drug regimens led to transient reductions in HIV viral loads and the evolution of HIV-1 variants with reduced susceptibility to ibalizumab. This report characterizes these variants by comparing the phenotypic susceptibilities and envelope (env) sequences of (i) paired baseline and on-treatment virus populations, (ii) individual env clones from selected paired samples, and (iii) env clones containing site-directed mutations. Viruses with reduced susceptibility to ibalizumab were found to exhibit reduced susceptibility to the anti-CD4 antibody RPA-T4. Conversely, susceptibility to soluble CD4, which targets the HIV-1 gp120 envelope protein, was enhanced. No changes in susceptibility to the fusion inhibitor enfuvirtide or the CCR5 antagonist maraviroc were observed. Functionally, viruses with reduced ibalizumab susceptibility also displayed high levels of infectivity relative to those of paired baseline viruses. Individual env clones exhibiting reduced ibalizumab susceptibility contained multiple amino acid changes in different regions relative to the paired baseline clones. In particular, clones with reduced susceptibility to ibalizumab contained fewer potential asparagine-linked glycosylation sites (PNGSs) in variable region 5 (V5) than did paired ibalizumab-susceptible clones. The reduction in ibalizumab susceptibility due to the loss of V5 PNGSs was confirmed by site-directed mutagenesis. Taken together, these findings provide important insights into resistance to this new class of antiretroviral drug.
authors.affiliation: Monogram Biosciences, 345 Oyster Point Blvd., South San Francisco, CA 94080, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Toma
authors.forename: Steven P
authors.initials: SP
authors.lastname: Weinheimer
authors.forename: Eric
authors.initials: E
authors.lastname: Stawiski
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Whitcomb
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Lewis
authors.forename: Christos J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000906:Antibodies; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D001216:Asparagine / Q000235:genetics / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D017900:Myoviridae; D017422:Sequence Analysis, DNA
chemical_list: D019380:Anti-HIV Agents; D000906:Antibodies; D000911:Antibodies, Monoclonal; D015699:HIV Envelope Protein gp120; D001216:Asparagine; C481504:ibalizumab