Challenges in Designing HIV Env Immunogens for Developing a Vaccine - Structure-Based Study of Viral Replication - page 338

-strands in the V1/V2 stem and
the C4 region of gp120. These regions are involved in binding of Env
to chemokine receptors. 49-52 Surprisingly, 17b and other CD4i mAbs
in their complete IgG form do not neutralize most primary isolates. 49
In contrast, Fab and single-chain fragments of these anti-CD4i mAbs
neutralize primary isolates, 48,53 suggesting that there may be space
constraints between the CD4i epitope on gp120 and the target cell
membrane. 54 Therefore, the entire IgG molecule may not be capable
of neutralization due to steric hindrance. 55,56 Further studies are
needed to confirm the accessibility of these conformational epitopes
for targeting them for vaccine application.
Contrary to earlier beliefs that epitopes in the variable domains are
isolate-specific (thus may not be appropriate targets for vaccine appli-
cation), recent structural studies suggest that V3 loop does contain
conserved functional epitopes , which may be targeted by vaccines.
The V3 loop is immunogenic and anti-V3 antibodies are induced early
during infection and after immunization. 3,57-59 However, a large pro-
portion of these antibodies are directed against linear epitopes in the
V3 loop, which serve as decoys for directing immune responses away
from conserved V3 regions. These antibodies neutralize homologous
isolates, but they have little or no neutralizing activity against diverse
primary isolates. 43,60 However, broadly neutralizing anti-V3 antibodies
directed against the conserved conformational epitopes have been
described. 61 The most broadly reactive of these neutralizing anti-V3
mAbs (such as 447-52D, 19b, and 2182) can neutralize a large pro-
portion of clade B primary isolates 39,62-64 and also have been shown to
neutralize viruses from clades A, F, C, and G, 65 suggesting that the epi-
topes recognized by these mAbs are conserved across clades.
Structural studies have shown that V3-loop has some constant fea-
tures, such as a relatively fixed size (30-35 aa), a conserved type-II turn
at its crown, a disulfide bond at its base, and a net positive charge. 66,67
These features are required in the V3 loop in order for it to interact
with the chemokine receptor. 68,69 It has been shown by Cao et al . that
deletion of V3 loop renders the virus non-infectious, suggesting that
V3 loop is essential. 70 Recently, structural studies have demonstrated
that V3 loops in R5 viruses are homologous to the

antibodies has now been mapped to β

β -hairpin structures