Biology Reference
In-Depth Information
Another factor that has the potential to limit the protective effect
of neutralizing antibodies is the emergence of neutralization escape
mutants.
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Richman and colleagues have shown that most patients
with primary HIV infection (0-39 months) developed significant
neutralizing antibody responses against the autologous virus; how-
ever, neutralizing responses against the laboratory-adapted isolates as
well as heterologous primary isolates are slow to develop and often
lower.
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The appearance of neutralization-resistant mutants indicates
that neutralizing antibody responses have a negative effect on the viral
replication during HIV infection. Thus, it appears that the virus is
under intense selection pressure to mutate neutralizing epitopes with-
out compromising functional aspects of the Env, such as binding to
the receptor and co-receptor to evade immune pressure. This adds
additional constraints in development of an effective anti-HIV vac-
cine. Despite this selective pressure, virus replication proceeds unhin-
dered in infected individuals. Thus, HIV Env can tolerate multiple
mutations and most of these mutations are positioned in variable
regions that contain several glycosylation sites. In general the number
of glycosylation sites in Env glycoprotein is relatively conserved across
subtypes and isolates, suggesting a pivotal role for carbohydrates in
Env function and structural integrity. This extensive glycosylation
provides the virus with some flexibility to modify neutralizing epi-
topes to evade the immune pressure simply by altering the glycosyla-
tion profile (adding, deleting or changing the position), without
perturbing the secondary structure.
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Strategies to Design Immunogens that may
Induce Neutralizing Antibodies of Protective
Specificities by Vaccination
It is evident that gp120 contains neutralizing epitopes and that anti-
bodies directed against these epitopes can protect against virus infection.
During the course of natural infection, primary neutralizing antibody
responses are induced in humans. However, the gp120 monomer
has been relatively ineffective at eliciting these primary isolate
neutralizing responses. Furthermore, a recently concluded phase III
