Increased Sensitivity to Broadly Neutralizing Antibodies of End-Stage Disease

Background: Induction of broadly neutralizing antibodies, such as the monoclonal antibodies IgGb12, 2F5 and 2G12, is the objective of most antibody-based HIV-1 vaccine undertakings. However, despite the relative conserved nature of epitopes targeted by these antibodies, mechanisms underlying the sensitivity of circulating HIV-1 variants to broadly neutralizing antibodies are not fully understood. Here we have studied sensitivity to broadly neutralizing antibodies of HIV-1 variants that emerge during disease progression in relation to molecular alterations in the viral envelope glycoproteins (Env), using a panel of primary R5 HIV-1 isolates sequentially obtained before and after AIDS onset. Principal Findings: HIV-1 R5 isolates obtained at end-stage disease, after AIDS onset, were found to be more sensitive to neutralization by TriMab, an equimolar mix of the IgGb12, 2F5 and 2G12 antibodies, than R5 isolates from the chronic phase. The increased sensitivity correlated with low CD4 T cell count at time of virus isolation and augmented viral infectivity. Subsequent sequence analysis of multiple env clones derived from the R5 HIV-1 isolates revealed that, concomitant with increased TriMab neutralization sensitivity, end-stage R5 variants displayed envelope glycoproteins (Envs) with reduced numbers of potential N-linked glycosylation sites (PNGS), in addition to increased positive surface charge. These molecular changes in Env also correlated to sensitivity to neutralization by the individual 2G12 monoclonal antibody (mAb). Furthermore, results from molecular modeling suggested that the PNGS lost at end-stage disease locate in the proximity to the 2G12 epitope. Conclusions: Our study suggests that R5 HIV-1 variants with increased sensitivity to broadly neutralizing antibodies, including the 2G12 mAb, may emerge in an opportunistic manner during severe immunodeficiency as a consequence of adaptive molecular Env changes, including loss of glycosylation and gain of positive charge. Citation: Borggren M, Repits J, Sterjovski J, Uchtenhagen H, Churchill MJ, et al. (2011) Increased Sensitivity to Broadly Neutralizing Antibodies of End-Stage Disease R5 HIV-1 Correlates with Evolution in Env Glycosylation and Charge. PLoS ONE 6(6): e20135. doi:10.1371/journal.pone.0020135 Editor: Mario A. Ostrowski, University of Toronto, Canada Received November 3, 2010; Accepted April 26, 2011; Published June 16, 2011 Copyright: 2011 Borggren 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: The work was supported by grants provided to MJ and AA from the Swedish Research Council, to MJ from the Swedish International Development Agency/Department for Research Cooperation, to EMF and JA from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement nu 2014332. Grants were also provided by the Physicians Against AIDS Research Foundation, Clas Groschinskys Foundation, The Royal Physiographic Society in Lund and Crafoords Foundation. MB and HU are supported by the EC FP6 grant 037611 (EUROPRISE), PRG was supported in part by a grant from the Australian National Health and Medical Research Council (433915). 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: [email protected] . These authors contributed equally to this work.