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 2F5 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 β-turn centered on gp41 residues 664DKW666; 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 Fab and 2F5 Fab′. Ab2/3H6 Fab binds to 2F5 Fab′ via a helix-like protrusion formed by residues 58(H)RYSPSLNTRL67(H) of the 2F5 Fab′ variable domain and proximal to but not overlapping with the gp41 664DKW666 epitope-binding pocket. This defines Ab2/3H6 as an anti-idiotypic antibody of the Ab2γ class, i.e., an antigen-inhibitable idiotype that does not carry the internal image of the linear primary gp41 662ELDKWAS668 epitope.