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Journal of Virology, March 2006, p. 3030-3041, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.3030-3041.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Simian Immunodeficiency Virus Engrafted with Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Epitopes: Replication, Neutralization, and Survey of HIV-1-Positive Plasma

Eloisa Yuste,1 Hannah B. Sanford,1 Jill Carmody,1 Jacqueline Bixby,1 Susan Little,5 Michael B. Zwick,2 Tom Greenough,3 Dennis R. Burton,2 Douglas D. Richman,4,5 Ronald C. Desrosiers,1 and Welkin E. Johnson1*

New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts 01772,1 Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037,2 University of Massachusetts Medical School, Worcester, Massachusetts 01655,3 VA San Diego Healthcare System,4 University of California—San Diego, La Jolla, California 920935

Received 20 September 2005/ Accepted 23 December 2005

To date, only a small number of anti-human immunodeficiency virus type 1 (HIV-1) monoclonal antibodies (MAbs) with relatively broad neutralizing activity have been isolated from infected individuals. Adequate techniques for defining how frequently antibodies of these specificities arise in HIV-infected people have been lacking, although it is generally assumed that such antibodies are rare. In order to create an epitope-specific neutralization assay, we introduced well-characterized HIV-1 epitopes into the heterologous context of simian immunodeficiency virus (SIV). Specifically, epitope recognition sequences for the 2F5, 4E10, and 447-52D anti-HIV-1 neutralizing monoclonal antibodies were introduced into the corresponding regions of SIVmac239 by site-directed mutagenesis. Variants with 2F5 or 4E10 recognition sequences in gp41 retained replication competence and were used for neutralization assays. The parental SIVmac239 and the neutralization-sensitive SIVmac316 were not neutralized by the 2F5 and 4E10 MAbs, nor were they neutralized significantly by any of the 96 HIV-1-positive human plasma samples that were tested. The SIV239-2F5 and SIV239-4E10 variants were specifically neutralized by the 2F5 and 4E10 MAbs, respectively, at concentrations within the range of what has been reported previously for HIV-1 primary isolates (J. M. Binley et al., J. Virol. 78:13232-13252, 2004). The SIV239-2F5 and SIV239-4E10 epitope-engrafted variants were used as biological screens for the presence of neutralizing activity of these specificities. None of the 92 HIV-1-positive human plasma samples that were tested exhibited significant neutralization of SIV239-2F5. One plasma sample exhibited >90% neutralization of SIV239-4E10, but this activity was not competed by a 4E10 target peptide and was not present in concentrated immunoglobulin G (IgG) or IgA fractions. We thus confirm by direct analysis that neutralizing activities of the 2F5 and 4E10 specificities are either rare among HIV-1-positive individuals or, if present, represent only a very small fraction of the total neutralizing activity in any given plasma sample. We further conclude that the structures of gp41 from SIVmac239 and HIV-1 are sufficiently similar such that epitopes engrafted into SIVmac239 can be readily recognized by the cognate anti-HIV-1 monoclonal antibodies.

* Corresponding author. Mailing address: New England Primate Research Center, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102. Phone: (508) 624-8041. Fax: (508) 786-3317. E-mail: wjohnson{at}hms.harvard.edu.

Journal of Virology, March 2006, p. 3030-3041, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.3030-3041.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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