Biology Reference
In-Depth Information
considering its highly immunogenic properties. The crystal structure
of SIV gp120 reveals a number of important facts.
First
, its overall
structure is very similar to that of HIV-1 gp120, especially the outer
domain of the protein.
76
Second
, neither the CD4 nor the co-recep-
tor binding site (BS) is properly formed in the unliganded state of the
Env. In the unliganded form, the two double-stranded anti-parallel
sheets are well separated and many residues that make up the CD4
BS are either masked or in different configuration compared to after
binding to CD4.
Third
, there is large displacement and rotation of
the inner domain and bridging sheet components upon CD4 binding:
(i) the three-strand anti-parallel sheet of the inner domain rotates by
30
-helix 1 shifts away from the outer domain,
and (iii) the tip of the V1
°
, (ii) the four-turn
α
/2 stem moves by over 40Å. These events
result in the formation of the bridging sheet. At present, the structure
of the V1/V2 loop is not known. However, it is thought to partially
mask the bridging sheet. Deeper insights into the native (i.e. un-trun-
cated) structures of gp120 could facilitate envelope-based vaccine
design. Now the efforts are being made by different groups including
ours to rationally design novel immunogens that may induce broadly
neutralizing antibody responses. So far, the focus has been to opti-
mize engineered Env structure for inducing potent antibody
responses against conserved functional epitopes by structure-based
targeted deglycosylation, by hyper-glycosylation, or by introducing
mutations/deletions in the bridging sheet.
α
Structure-based Targeted Deglycosylation
The extensive glycosylation of Env is likely to be involved in immune
evasion. Based on crystal structure it seems that the outer domain of
gp120 is heavily glycosylated, as shown by Wyatt and colleagues
77
(Fig. 8). Despite being most exposed to antibodies, this region of Env
is known as “silent face” because it seldom induces neutralizing anti-
body responses. Thus, the sugar moieties may be shielding critical
neutralization epitopes. Malenbaum
et al
. have demonstrated that the
removal of glycosylation at position 301 resulted in an increased neu-
tralizing sensitivity of HIV-1 to CD4 BS antibodies.
168
Furthermore,
