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against the CD4 BS have been developed that can neutralize T-cell
line-adapted isolates, 35,36 suggesting that these epitopes are relatively
well exposed on the virion surface. 37 The most potent and well-char-
acterized monoclonal antibody against the CD4BS, b12, 38 neutralizes
a broad range of primary isolates and confirms the critical role of the
CD4BS in HIV-1 infection. 39-41 Interestingly, other CD4BS mono-
clonal antibodies such as 559/64D, 15e, F105, b3, and b6 do not
neutralize primary isolates. 42,43 The reasons for this discrepancy are
not yet understood, but b12 differs from all the other CD4BS anti-
bodies in its sensitivity to V1-V2 loop deletion. 44 It is not known if
b12 contacts the V1-V2 loop or if the sensitivity is due to an indirect
effect of conformational rearrangements following V1-V2 deletions.
High resolution crystal structure of b12 has been solved, and a key
feature of the antibody-combining site is the protruding, finger-like
long CDR H3 that can penetrate the recessed CD4-binding site of
gp120, which is quite effective in neutralizing the virus. A docking
model of b12 and gp120 reveals severe structural constraints that
explain the extraordinary challenge in eliciting effective neutralizing
antibodies similar to b12. The structure, together with mutagenesis
studies, provides a rationale for the extensive cross-reactivity of b12
and is a valuable framework for the design of HIV-1 vaccines capable
of eliciting b12-like activity. 45
After primary attachment of virus to the T-cell surface, gp120
interacts with chemokine receptors CCR5 or CXCR4, which are the
most common cellular co-receptors for HIV-1. The interaction of
Env to CD4 induces the conformational change in gp120 and gp41
(Fig. 5B). As a result, the co-receptor binding site and fusogenic
region of gp41 are displayed (Fig. 5C), leading to the fusion of viral
and cellular membranes (Fig. 5D) and, release of the viral core parti-
cles in to the cytoplasm of the cell. Therefore CD4-inducible epitopes
of Env may represent another target for immune intervention .
Antibodies that show reactivity toward HIV Env when it is complexed
with soluble CD4 (sCD4) were found in HIV-1-infected individu-
als, 46 suggesting that these epitopes are immunogenic. Several such
human mAbs have been identified, including 17b, 48D, CG10, 23E,
and X5. 47-49
The region recognized by these anti-CD4i monoclonal
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