Crystal structure of the complex between the Fab′ fragment of the cross-neutralizing anti-HIV-1 antibody 2F5 and the Fab fragment of its anti-idiotypic antibody 3H6

The monoclonal antibody 2175 neutralizes a broad range of human immunodeficiency virus-1 isolates via a conserved epitope on the viral glycoprotein gp41. The conformation of the principal epitope is a type I beta-turn centered on gp41 residues (DKW666)-D-664; in addition, binding studies indicate that residues N- and C-terminal to this core as well as structurally more distant parts of gp41 also contribute to the interaction. Ab2/3H6 is an anti-idiotypic antibody that inhibits the interaction between 2F5 and gp41 and as such, Ab2/3H6 may, in principle, possess a paratope that mimics the gp41 epitope. To establish the potential of Ab2/3H6 to serve as a guide for the design of vaccine components against human immunodeficiency virus, we investigated the crystal structure of the heterodimeric complex of Ab2/3H6 F-ab and 2F5 F-ab'. Ab2/3H6 F-ab binds to 2F5 F-ab' via a helix-like protrusion formed by residues (RYSPSLNTRL67(H))-R-58(H) of the 2F5 F-ab' variable domain and proximal to but not overlapping with the gp41 (DKW666)-D-664 epitope-binding pocket. This defines Ab2/3H6 as an anti-idiotypic antibody of the Ab2 gamma class, i.e., an antigen-inhibitable idiotype that does not carry the internal image of the linear primary gp41 (662)ELDKWAS(668) epitope. (C) 2008 Elsevier Ltd. All rights reserved.