Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks 
HIV-1 infection and targets an epitope in the second domain of CD4 without 
interfering with immune functions mediated by interaction of CD4 with major 
histocompatibility complex (MHC) class II molecules. We report here the crystal 
structure of ibalizumab Fab fragment in complex with the first two domains 
(D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the 
BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and 
MHC-II binding sites. No major conformational change in CD4 accompanies binding 
to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively 
block viral infection, suggesting that it does not need to crosslink CD4 to 
exert antiviral activity. While gp120-induced structural rearrangements in CD4 
are probably minimal, CD4 structural rigidity is dispensable for ibalizumab 
inhibition. These results could guide CD4-based immunogen design and lead to a 
better understanding of HIV-1 entry.