Epitope Mapping of Broadly Neutralizing HIV-2 Human Monoclonal Antibodies

Rui Kong,^a,b,* Hui Li,^b Ivelin Georgiev,^c Anita Changela,^c Frederic Bibollet-Ruche,^b Julie M. Decker,^a Sarah L. Rowland-Jones,^d Assan Jaye,^e Yongjun Guan,^f George K. Lewis,^f Johannes P. M. Langedijk,^g,* Beatrice H. Hahn,^b Peter D. Kwong,^c James E. Robinson,^h, and George M. Shaw^b

Departments of Microbiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA,^a Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA,^b Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA,^c Weatherall Institute of Molecular Medicine, Medical Research Council Human Immunology Unit, John Radcliffe Hospital, Oxford, United Kingdom,^d Medical Research Council (United Kingdom) Laboratories, Fajara, The Gambia,^e Institute of Human Virology, School of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA,^f Pepscan Therapeutics, Lelystad, The Netherlands,^g Department of Pediatrics, Tulane University Medical Center, New Orleans, Lousiana, USA,^h

Abstract: Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930–946, 2012; R. Kong, et al., J. Virol. 86:947–960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961–971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2_7312A and HIV-2_ST. Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2_UC1. The median 50% inhibitory concentrations (IC₅₀s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 μg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic in vivo and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity.

Address correspondence to George M. Shaw, shawg{at}upenn.edu.

Published ahead of print 29 August 2012

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock.

M. Lopker, J. Easlick, S. Sterrett, J. M. Decker, H. Barbian, G. Learn, B. F. Keele, J. E. Robinson, H. Li, B. H. Hahn, et al. (2013)
J. Virol. 87, 5477-5492
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