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PMID: 17567707 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

In vivo and in vitro escape from neutralizing antibodies 2G12, 2F5, and 4E10.

Journal of virology ·Vol. 81 ·No. 16 ·2007-08-00 ·Pages 8793-808

Manrique A, Rusert P, Joos B, Fischer M, Kuster H, Leemann C, Niederöst B, Weber R, Stiegler G, Katinger H, Günthard HF, Trkola A

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.

MeSH Terms
Amino Acid Sequence Antibodies, Monoclonal/immunology,pharmacology,therapeutic use Drug Resistance, Viral/genetics Epitopes/immunology Glycosylation HIV/drug effects,genetics,immunology HIV Antibodies/immunology,pharmacology,therapeutic use HIV Infections/drug therapy,immunology Humans Molecular Sequence Data Mutation Sequence Analysis, RNA
Chemicals
Antibodies, Monoclonal Epitopes HIV Antibodies
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Manrique Amapola
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
Rusert Peter
Joos Beda
Fischer Marek
Kuster Herbert
Leemann Christine
Niederöst Barbara
Weber Rainer
Stiegler Gabriela
Katinger Hermann
Günthard Huldrych F
Trkola Alexandra
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.00598-07
Published
2007-08-00
Epub
2007-00-13
Pages
8793-808
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1951363
Subset
IM
Databases
GENBANK
EF643652, EF643653, EF643654, EF643655, EF643656, EF643657, EF643658, EF643659, EF643660, EF643661, EF643662, EF643663, EF643664, EF643665, EF643666, EF643667, EF643668, EF643669, EF643670, EF643671, EF643672, EF643673, EF643674, EF643675, EF643676, EF643677, EF643678, EF643679, EF643680, EF643681, EF643682, EF643683, EF643684, EF643685, EF643686, EF643687, EF643688, EF643689, EF643690, EF643691, EF643692, EF643693, EF643694, EF643695
External Links
PubMed source DOI: 10.1128/JVI.00598-07 PMC Full Text View journal details
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