Expansion of epitope cross-reactivity by anti-idiotype modulation of the primary humoral response

• Published in: Molecular immunology 2000-01, Vol.37 (1), p.53-58
• Main Authors: Denisova, G.F., Zerwanitzer, M., Denisov, D.A., Spectorman, E., Mondor, I., Sattentau, Q., Gershoni, J.M.
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Amino Acid Sequence; Animals; Anti-idiotypic network; Antibodies, Anti-Idiotypic - immunology; Antibody Formation; Antigen genetic drift; Cross Reactions; Epitopes - immunology; HIV Envelope Protein gp120 - immunology; HIV-1 - immunology; human immunodeficiency virus 1; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Phage display epitope library
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/S0161-5890(00)00022-5

The primary humoral response produces antigen-specific antibodies so to clear the initial infection, and generates a population of corresponding memory cells to prevent infection by future encounters with the same pathogen. The continuous genetic modification of a pathogen's exterior, however, is one mechanism used to evade the immune defenses of its host. Here we describe a novel means, involving anti-idiotypic antibodies, by which the host can counteract such pathogen genetic alterations by modulation of its primary humoral response. An autoimmune response against primary antibodies, Ab1's, creates anti-idiotypic antibodies (Ab2's), some of which (designated Ab2α) are able to bind the Ab1/antigen complex. We have discovered that binding of Ab2α to its corresponding Ab1 can expand Ab1's ability to bind variations of its antigen. This expanded epitope cross-reactivity is shown not only to increase the binding activity of Ab1 but also its ability to neutralize a variant infectious virus. MAb M77 is an Ab1, which is highly strain-specific for the HIV-1 envelope protein gp120 IIIB. This Ab1 can be rendered cross-reactive and neutralizing for an otherwise resistant HIV strain by its interaction with a unique anti-idiotypic Ab2α (GV12). Furthermore, molecular characterization of this expanded cross-reactivity was accomplished using combinatorial phage display peptide libraries.