Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
Receptor-mediated activation of the viral envelope involves the exposure of novel neutralizing envelope determinants.
Int Conf AIDS. 1992 Jul 19-24;8(1):Mo14 (abstract no. MoA 0048). Unique Identifier : AIDSLINE ICA8/92400008 Allan JS; Whitehead EM; Strout K; Shuler K; Kanda P; Southwest Foundation for Biomedical Research, San Antonio, TX.
Abstract:
OBJECTIVES: Interaction of simian immunodeficiency viruses from African green monkeys (SIVagm) with soluble receptor molecules (sCD4) results in profound enhancement (100-fold) of in vitro infection in contrast to sCD4 blocking of HIV-1 and HIV-2. We have previously shown that this enhancing effect is a direct consequence of gp120 interaction with CD4 and that viral enhancement could be neutralized with antibodies from infected green monkeys once virus has been treated with sCD4. This finding suggested that sCD4 induces important conformational changes in the virion spike (activation) and that this transitional state is part of the entry process. Mapping of neo-neutralizing domains on SIVagm may shed some light into the overall mechanisms of viral entry for this family of immunodeficiency viruses and provide for novel approaches in vaccine and therapeutic strategies. METHODS: To define neutralizing domains on SIVagm, monoclonal antibodies were prepared by immunization of mice with whole virus. Monoclonal antibodies with defined specificity were identified by screening in a functional assay for neutralization of sCD4-mediated enhancement of SIVagm infection. In a second approach, we synthesized synthetic peptides to defined epitopes of SIVagm gp120 and gp36, prepared hyperimmune sera from immunized rabbits, and antibodies were assayed for neutralization of sCD4-treated SIVagm RESULTS: Monoclonal antibodies were produced that functionally blocked sCD4 mediated enhancement of SIVagm and mapped to gp120. By radioimmunoprecipitation analysis (RIPA), binding of one antibody (AG1.0) to gp120 was enhanced by prior incubation of virus with sCD4 indicating that this neutralizing determinant was further exposed upon sCD4 activation. In addition, polyclonal antibodies to a gp120 synthetic peptide were also found to neutralize this sCD4-mediated enhancement of SIVagm. Remarkably, monoclonal antibody (AG1.0) also bound to this synthetic peptide providing convincing evidence for the identification of an immunodominant neutralizing epitope involved either directly or indirectly in viral entry. CONCLUSIONS: The study of receptor-mediated enhancement of SIVagm has allowed for the determination of novel neutralizing epitope(s) that are exposed upon receptor-binding. Such novel domains may be involved in secondary events in viral fusion and may prove useful in the design of more effective in vaccines and post-infection immunotherapeutic regimens.
Keywords: Animal Antibodies, Monoclonal/*IMMUNOLOGY Antibodies, Viral/*IMMUNOLOGY Antigens, CD4/*METABOLISM Cercopithecus aethiops/MICROBIOLOGY Cytopathogenic Effect, Viral Epitopes/*IMMUNOLOGY HIV Envelope Protein gp120/*IMMUNOLOGY Membrane Fusion Mice Neutralization Tests Peptide Fragments/IMMUNOLOGY Protein Conformation SIV/*IMMUNOLOGY/METABOLISM Virion/IMMUNOLOGY/METABOLISM/ULTRASTRUCTURE ABSTRACT 921230
M92C5339
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
