2010-3-23 4 E 10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms

Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope. Citation: Nakamura KJ, Gach JS, Jones L, Semrau K, Walter J, et al. (2010) 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms. PLoS ONE 5(3): e9786. doi:10.1371/journal.pone.0009786 Editor: Douglas F. Nixon, University of California San Francisco, United States of America Received January 29, 2010; Accepted February 10, 2010; Published March 23, 2010 Copyright: 2010 Nakamura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health Cellular, Biochemical, and Molecular Sciences Training Program Grant (T 32 067587), National Institute of Child Health and Human Development (HD 57161, HD 39611, and HD 40777), National Institute of Allergy and Immunology (AI69993), International Maternal Pediatric Adolescent AIDS Trials Group U01 AI068632 and Austrian Science Fund Grant J2845-B13. GMA is an Elizabeth Glaser Pediatric AIDS Foundation Scientist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: galdrovandi@chla.usc.edu ¤ Current address: Department of Plant Pathology and Microbiology, University of California, Riverside, California, United States of America