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HIV-1 Envelope Glycoprotein Resistance to Monoclonal Antibody 2G12 Is Subject-Specific and Context-Dependent in Macaques and Humans

Malherbe, DC and Sanders, RW and van Gils, MJ and Park, B and Gomes, MM and Schuitemaker, H and Barnett, S and Haigwood, NL (2013) HIV-1 Envelope Glycoprotein Resistance to Monoclonal Antibody 2G12 Is Subject-Specific and Context-Dependent in Macaques and Humans. PLoS One.

Abstract

HIV-1 Envelope (Env) protein is the sole target of neutralizing antibodies (NAbs) that arise during infection to neutralize autologous variants. Under this immune pressure, HIV escape variants are continuously selected and over the course of infection Env becomes more neutralization resistant. Many common alterations are known to affect sensitivity to NAbs, including residues encoding potential N-linked glycosylation sites (PNGS). Knowledge of Env motifs associated with neutralization resistance is valuable for the design of an effective Env-based vaccine so we characterized Envs isolated longitudinally from a SHIV<sub>SF162P4</sub> infected macaque for sensitivity to neutralizing monoclonal antibodies (MAbs) B12, 2G12, 4E10 and 2F5. The early Env, isolated from plasma at day 56 after infection, was the most sensitive and the late Env, from day 670, was the most resistant to MAbs. We identified four PNGS in these Envs that accumulated over time at positions 130, 139, 160 and 397. We determined that removal of these PNGS significantly increased neutralization sensitivity to 2G12, and conversely, we identified mutations by in silico analyses that contributed resistance to 2G12 neutralization. In order to expand our understanding of these PNGS, we analyzed Envs from clade B HIV-infected human subjects and identified additional glycan and amino acid changes that could affect neutralization by 2G12 in a context-dependent manner. Taken together, these in vitro and in silico analyses of clade B Envs revealed that 2G12 resistance is achieved by previously unrecognized PNGS substitutions in a context-dependent manner and by subject-specific pathways. 2013 Malherbe et al

Item Type: Article
Additional Information: pubid: 112 nvp_institute: NIBR contributor_address: (Malherbe, Gomes, Haigwood) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United States (Sanders, van Gils) Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, Netherlands (Sanders) Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, United States (Park) Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, United States (Schuitemaker) Laboratory of Viral Immune Pathogenesis, Department of Experimental Immunology, Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, Netherlands (Schuitemaker) Crucell, Leiden, Netherlands (Barnett) Novartis Institutes for Biomedical Research, Cambridge, MA, United States
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21950

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