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Journal of Virology, August 2007, p. 8793-8808, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00598-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vivo and In Vitro Escape from Neutralizing Antibodies 2G12, 2F5, and 4E10{triangledown}

Amapola Manrique,1 Peter Rusert,1 Beda Joos,1 Marek Fischer,1 Herbert Kuster,1 Christine Leemann,1 Barbara Niederöst,1 Rainer Weber,1 Gabriela Stiegler,2 Hermann Katinger,2 Huldrych F. Günthard,1 and Alexandra Trkola1*

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland,1 Polymun Scientific, Vienna, Austria2

Received 21 March 2007/ Accepted 28 March 2007

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.

* Corresponding author. Mailing address: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Phone: 41 44 255 5976. Fax: 41 44 255 3291. E-mail: alexandra.trkola{at}usz.ch

{triangledown} Published ahead of print on 13 June 2007.

Journal of Virology, August 2007, p. 8793-8808, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00598-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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