(A) This schematic diagram shows the linear sequence of gp120 where five relatively constant regions, C1 to C5, and five variable regions, V1 to V5, can be traced
to N terminus to C terminus. The CD4-binding site (CD4bs) (highlighted in brown) and the chemokine receptor binding site (CRbs; green) are conformational surfaces
formed with discontinuous segments from different gp120 regions (modified from ref [5]). (B) MAb binding to gp120 induces conformational changes that modulate
the exposure and stability of different gp120 epitopes. This effect is Fab-mediated as it is dependent on the fine specificity of the mAb. Our immune complex vaccine
strategy takes advantage of this modulatory activity to augment the immunogenicity of V3 and other neutralizing epitopes on gp120. For examples, immune complexes
made of gp120 and anti-CD4 binding site mAbs enhance antigenicity and immunogenicity of V3 epitopes [40,55]. Similarly, gp120/anti-V2 mAb complexes display
enhanced V3 reactivity [40]. Other gp120/mAb complexes have been identified that exhibit higher reactivity for epitopes in the CD4-binding site and the bridging
sheet of the CRbs [57,70]. In support of this, conformational differences are observed in the crystallographic structures of gp120 bound by CD4 and various mAbs
[22,52,71-73]. However, the extent of structural alterations induced by these ligands remains unclear as no crystal structure of unliganded gp120 is available. (C) The
Fc fragment of gp120/mAb complex interacts with Fc receptors on antigen-presenting cells to facilitate antigen uptake and processing for MHC class II presentation
to helper T cells [42]. Hence, both Fab- and Fc-mediated activities play important roles in regulating the capacity of gp120/mAb complex vaccines to elicit effective
immune responses against HIV.