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

The primary humoral response produces antigen-specific antibodies so to cle ar the initial infection, and generates a population of corresponding memor y cells to prevent infection by future encounters with the same pathogen. T he continuous genetic modification of a pathogen's exterior, however, is on e 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 h umoral response. An autoimmune response against primary antibodies, Abl's, creates antiidiotypic antibodies (Ab2's), some of which (designated Ab2 alp ha) are able to bind the Ab1/antigen complex. We have discovered that bindi ng of Ab2a to its corresponding Abl can expand Abl's ability to bind variat ions of its antigen. This expanded epitope cross-reactivity is shown not on ly to increase the binding activity of Abl but also its ability to neutrali ze a variant infectious virus. MAb M77 is an Abl, which is highly strain-sp ecific for the HIV-1 envelope protein gp120(IIIB) This Abl can be rendered cross-reactive and neutralizing for an otherwise resistant HIV strain by it s interaction with a unique anti-idiotypic Ab2 alpha (GV12). Furthermore, m olecular characterization of this expanded cross-reactivity was accomplishe d using combinatorial phage display peptide libraries. (C) 2000 Published b y Elsevier Science Ltd. All rights reserved.