AIDS/HIV, Molecular and Cell Biology
cellular receptor may be neutralizing and
the site at which they bind on the viral
protein provides strong clues as to the im-
portant regions of SU involved in viral
entry. In particular, the V3 loop is a major
target for neutralizing antibody. A second
region on gp120, which is involved in both
CD4 and chemokine receptor binding, is
another neutralization target. However, V3
loop neutralizing antibodies often appear
to be more effective against laboratory
strains of HIV than primary clinical iso-
lates. It is possible that this relates to the
different conformation of the envelope in
in vitro
adapted strains in which the
lack of immune selection pressure has al-
lowed a more open structure that favors
rapid cellular entry.
In vivo
ture would predispose to the blockade by
neutralizing antibodies and may be disad-
Other evidence suggesting that antibod-
ies are of relatively low importance is the
fact that some individuals in whom the
immune response do not have high lev-
els of neutralizing antibody. In addition,
passive protection using antibodies in ani-
mal models is only effective when they are
present in very high titer. There is some
evidence that high titers of neutralizing an-
tibody may be associated with a lower ‘‘set
point.’’ The immense variability of the viral
envelope facilitates immunological escape
of the virus. This may occur either by
amino acid variability or by modiFcation
of envelope glycosylation.
Cytotoxic T-cell responses can be de-
tected before the antibody response and
have long been considered one of the ma-
jor immunological defenses against HIV.
T cells can kill virus infected cells
by speciFc recognition of the HIV pep-
on the surface of the infected cell.
, CTLs can eliminate infected cells
even before new viruses have been pro-
duced. A second effect involves the release
-chemokine mediators, which, as pre-
viously mentioned, are themselves able to
bind to their natural ligand CCR5 and
block the use of this protein by HIV for
infection of the cell. The strong correla-
tion between appearance of CD8
T cells
and the decline in viral replication in the
early stages together with data on adoptive
transfer in humans and CD8 depletion ex-
periments in monkeys, which leads to a
sustained increase in viral load, conFrms
the critical role played by this arm of the
immune response in combating infection.
The signature of HIV infection is the
decline in CD4 lymphocytes. The mecha-
nisms of destruction of CD4 lymphocytes
are probably many and varied as described
earlier. Production of HIV with its gp120
within a cell that is already making CD4
may lead to protein aggregation within the
cell and dysfunction leading to apoptosis.
This can be observed
in vitro
as single cell
killing. Expression of gp120 on the surface
of the cell may induce fusion of that cell
with a CD4
cell. This latter phenomenon
is also seen
in vitro
and leads to killing by
syncitia formation. Passive binding of shed
gp120 on to the CD4 proteins of immune
competent cells may lead to them being
a target for immunological clearance and
the gp120 itself may have adverse effects.
The cytotoxic T-cell response, clearing in-
fected cells, is probably responsible for a
very large proportion of the destruction of
infected cells. Thus, a number of di-
rect and indirect mechanisms contribute
to the loss of the CD4 cell population.
Individuals whose disease progresses
sors – LTNPs) have clearly been shown
to have powerful T-cell responses against
HIV with the CD4 lymphoproliferative
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