Simian immunodeficiency virus engrafted with human immunodeficiency virus type 1 (HIV-1)-specific epitopes: replication, neutralization, and survey of HIV-1-positive plasma.

TitleSimian immunodeficiency virus engrafted with human immunodeficiency virus type 1 (HIV-1)-specific epitopes: replication, neutralization, and survey of HIV-1-positive plasma.
Publication TypeJournal Article
Year of Publication2006
AuthorsYuste E, Sanford HB, Carmody J, Bixby J, Little S, Zwick MB, Greenough T, Burton DR, Richman DD, Desrosiers RC, Johnson WE
JournalJ Virol
Volume80
Issue6
Pagination3030-41
Date Published2006 Mar
ISSN0022-538X
KeywordsAnimals, Antibodies, Monoclonal, Antibody Specificity, Cell Line, Epitopes, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Neutralization Tests, Peptide Fragments, Simian Immunodeficiency Virus, Virus Replication
Abstract

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.

DOI10.1128/JVI.80.6.3030-3041.2006
Alternate JournalJ. Virol.
PubMed ID16501112
PubMed Central IDPMC1395451
Grant ListAI 33292 / AI / NIAID NIH HHS / United States
AI 36214 / AI / NIAID NIH HHS / United States
AI043638 / AI / NIAID NIH HHS / United States
AI047745 / AI / NIAID NIH HHS / United States
AI058725 / AI / NIAID NIH HHS / United States
AI062524 / AI / NIAID NIH HHS / United States
AI27670 / AI / NIAID NIH HHS / United States
AI29164 / AI / NIAID NIH HHS / United States
AI50421 / AI / NIAID NIH HHS / United States
R01 AI057039 / AI / NIAID NIH HHS / United States
RR00168 / RR / NCRR NIH HHS / United States