title: In vivo and in vitro escape from neutralizing antibodies 2G12, 2F5, and 4E10.
abstract: Recently, passive immunization of human immunodeficiency virus (HIV)-infected individuals with monoclonal antibodies (MAbs) 2G12, 2F5, and 4E10 provided evidence of the in vivo activity of 2G12 but raised concerns about the function of the two membrane-proximal external region (MPER)-specific MAbs (A. Trkola, H. Kuster, P. Rusert, B. Joos, M. Fischer, C. Leemann, A. Manrique, M. Huber, M. Rehr, A. Oxenius, R. Weber, G. Stiegler, B. Vcelar, H. Katinger, L. Aceto, and H. F. Gunthard, Nat. Med. 11:615-622, 2005). In the light of MPER-targeting vaccines under development, we performed an in-depth analysis of the emergence of mutations conferring resistance to these three MAbs to further elucidate their activity. Clonal analysis of the MPER of plasma virus samples derived during antibody treatment confirmed that no changes in this region had occurred in vivo. Sequence analysis of the 2G12 epitope relevant N-glycosylation sites of viruses derived from 13 patients during the trial supported the phenotypic evaluation, demonstrating that mutations in these sites are associated with resistance. In vitro selection experiments with isolates of four of these individuals corroborated the in vivo finding that virus strains rapidly escape 2G12 pressure. Notably, in vitro resistance mutations differed, in most cases, from those found in vivo. Importantly, in vitro selection with 2F5 and 4E10 demonstrated that resistance to these MAbs can be difficult to achieve and can lead to selection of variants with impaired infectivity. This remarkable vulnerability of the virus to interference within the MPER calls for a further evaluation of the safety and efficacy of MPER-targeting therapeutic and vaccination strategies.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Amapola
authors.initials: A
authors.lastname: Manrique
authors.forename: Peter
authors.initials: P
authors.lastname: Rusert
authors.forename: Beda
authors.initials: B
authors.lastname: Joos
authors.forename: Marek
authors.initials: M
authors.lastname: Fischer
authors.forename: Herbert
authors.initials: H
authors.lastname: Kuster
authors.forename: Christine
authors.initials: C
authors.lastname: Leemann
authors.forename: Barbara
authors.initials: B
authors.lastname: Niederöst
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
authors.forename: Gabriela
authors.initials: G
authors.lastname: Stiegler
authors.forename: Hermann
authors.initials: H
authors.lastname: Katinger
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics*; D000939:Epitopes / Q000276:immunology; D006031:Glycosylation; D006678:HIV / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017423:Sequence Analysis, RNA
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015483:HIV Antibodies