112
AIDS/HIV, Molecular and Cell Biology
from then on there is a very slow but
progressive decline.
Calculations of the quantity of virus be-
ing produced during this time and the rate
of lymphocyte destruction/regeneration
have generated the remarkable Fgures that
around 10
9
–10
10
viruses are produced and
destroyed each day. This is probably an
underestimate. The lymphocyte turnover
is also around 10
9
per day, but while the
viral load may be constant or may rise, the
lymphocyte count slowly falls such that
thereisane
tlosso
faround10
6
lympho-
cytes per day. The fall in lymphocyte count
correlates with a progressive decline in im-
munological competence and is a marker,
if not the cause, of the eventual break-
down in immune competence. At this
stage, the number of infected cells in the
blood is very low, at around 1 in 10
5
.This
might suggest that virus mediated lym-
phocyte destruction is less important at
this stage, although localized destruction
in lymph nodes would be difFcult to de-
tect. Immune clearance of infected cells,
however, may be the dominant force af-
fecting lymphocyte numbers. Depending
on the success of the immune response
in controlling the virus, the length of time
between seroconversion and immunode-
Fciency may be anything from 2 up to
12+ years. However, as yet, although there
are examples of very slow progressors,
there is no evidence of complete control
of viral infection by the immune system
once the virus has established itself. At
the late stages of the disease, the predom-
inant type of virus appears to change with
the emergence of faster replicating T-cell
tropic (X4) variants.
Symptomatic
immunodeFciency
be-
comes apparent when the lymphocyte
count falls below 200
×
10
9
L
1
,a
twh
ich
point the individual is at very high
risk of opportunistic infection and the
development of unusual malignancies.
The fall in lymphocyte count correlates
with a loss of control over viral replication
and a rise in detectable virus in the
circulation in the absence of antiretroviral
therapy. Death from an overwhelming
infection or an uncontrolled malignancy
usually occurs within two to three years of
the onset of the severe immunodeFciency
even with treatment of the individual
infections and cancers.
As will be described later, the advent of
antiretroviral therapy has transformed the
natural history of disease in the western
world. Pharmacological control of virus
replication leads to a fall in viral load
and a corresponding rise in the CD4
lymphocyte count. This leads to a reversal
of the loss of immunocompetence, which,
although it may not be complete, is
enough to signiFcantly reduce the risk of
opportunistic infection.
5
Immune Response to HIV
±ollowing the initial peak of virus in the
circulation after infection, the viral load
declines to a set point, which, on average,
is around 30 000 copies per milliliter.
If it is higher than this, the onset of
AIDS is quicker and vice versa. It appears
that qualitative and quantative parameters
of the immune response determine this
set point. A broad antibody response
develops within the Frst three months
of infection with speciFcity for some
of the structural proteins such as Gag.
Antibodies to Envelope and Polymerase
proteins appear swiftly thereafter, and
the regulatory and accessory proteins also
trigger an antibody response.
Antibodies interfering with interaction
between the envelope protein and the
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