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in CC chemokines (CCL3 [MIP-1
], and CCL5
[RANTES]), but homologous to the CXC chemokine CXCL12
(SDF-1) in X4 viruses. 71 In addition, Yonezawa et al . have replaced the
V3 loop of the X4 virus with a 43-amino acid region of SDF-1, which
includes the
α
], CCL4 [MIP-1
β
-hairpin, and demonstrated that infectivity was main-
tained. 72 Together, these data suggest a critical role for the V3 region in
virus infectivity and provide a potential rationale for designing immuno-
gens that induce antibodies to the conserved V3 motif. However, these
concepts need to be evaluated in pre-clinical studies for their ability to
induce cross-reactive neutralizing antibody responses.
β
Carbohydrate-dependent Epitopes in gp120
HIV Env is heavily glycosylated, with approximately 50% of its mass
due to carbohydrates. 73 It has been demonstrated that glycosylation
is critical for the Env-CD4 interaction, since non-glycosylated Env
protein (env2-3) does not bind to CD4. 74,75 Thus, carbohydrate moi-
eties on Env appear to provide a functional conformation to Env crit-
ical for its interaction with CD4. In addition, based on the
crystallization studies of gp120, it appears that the exposed face of
gp120 is heavily glycosylated (Fig. 4A). Even in context of trimer,
molecular modeling studies suggest that the heavily glycosylated part
of the molecule is exposed to the immune system. 76,77 These data sug-
gest that extensive glycosylation may shield critical neutralizing epi-
topes. Therefore, it is not surprising that antibodies recognizing
carbohydrate-dependent epitopes on Env are not readily induced dur-
ing the course of natural infection. The best-studied anti-carbohy-
drate antibody with broadly neutralizing activity is mAb 2G12 , which
targets a cluster of carbohydrate moieties in gp120. 19,78 This mAb has
broad neutralizing activity both against T-cell line-adapted and pri-
mary HIV-1 isolates. 19,79 However, its reactivity may be limited, as it
does not neutralize subtype C isolates. 80 The unconventional configu-
ration of this mAb 81 and the poor immunogenicity of the epitope
recognized by 2G12 79 raise questions about the mode of neutraliza-
tion (since the epitope recognized by this mAb has been localized on
the immunologically silent face of gp120) and how to design an
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