114
AIDS/HIV, Molecular and Cell Biology
response correlating well with success-
ful suppression of the viral load. Whether
these cells act independently or through
enhancement of CD8
+
CTL killing is
not clear and it may be a combina-
tion of both. Apart from speciFc genetic
variants such as the CCR5 truncation mu-
tation described earlier, there does appear
to be some genetic influences in that
certain HLA alleles HLAB35 and CW4
are associated with more rapid disease
progression, and certain other polymor-
phisms in chemokines and chemokine
receptor genes may influence responses
to therapeutic strategies and vaccination.
The immune response is capable of a
measure of control of HIV replication in
all patients, and in some, there is very sig-
niFcant delay in the onset of AIDS. Recent
evidence suggests that not only does the
ability to mount an immune response de-
cline as disease progresses but the ability
to regenerate this when antiretroviral treat-
ment is started also declines the longer
the initiation of treatment is delayed. In-
deed, treatment during the early stages
of infection at seroconversion has been
correlated with a much better long-term
CD4 lymphoproliferative response. Thus,
early treatment might lead to the ability to
maintain a strong CD4 cell response and
this might provide the possibility of pow-
erful long-term control of viral replication.
Against this is the risk of generating drug
resistance early in infection and the loss of
utility of the limited range of chemother-
apeutic agents when they may be more
useful at a later stage.
6
Drug Therapy of HIV
Antiviral drugs are commonly targeted
a
tv
i
r
a
len
z
ym
e
s
.Th
i
si
sth
ec
a
s
ew
i
th
HIV in which the Frst two types of
highly successful pharmacotherapies have
been directed to inhibit the actions of
the viral reverse transcriptase gene and
the protease gene. Reverse transcriptase
is clearly a virus-speciFc process since
the cell does not have any functional
RNA-dependent DNA polymerase activity.
The reverse transcriptase enzyme does not
have proof-reading capability and while, as
mentioned later, this may be an advantage
to the virus in generating variants, it
also is an Achilles’ heel for the virus
in that nucleoside analogs that mimic
the bases that the enzyme is attempting
to incorporate into the DNA chain can
substitute for these and once inserted
cannot be excised. Pyrimidine analogs
have been particularly effective and they
appear to act both by inhibiting the enzyme
and by chain termination. They require
phosphorylation within the cell to form
triphosphates. Another class of drug that
inhibits RT is the nonnucleoside reverse
transcriptase inhibitors (NNRTIs), which
bind to reverse transcriptase away from
the active site but are not incorporated
into the transcript. A third major class of
antiretroviral drugs are those inhibiting
the viral protease. These take advantage of
the target peptide sequence of the aspartyl
protease of HIV, being slightly different
from cellular homologs of this enzyme.
Predictably, however, the speciFcity of
these drugs is somewhat lower than RT
inhibitors and they are associated with a
greater number of side effects, probably
relating to effects on cellular proteases.
Newer classes of drugs are being developed
including those that may inhibit viral entry,
viral integration, and viral export. Injection
of a peptide, which interferes with the
formation of the fusogenic envelope of the
virus and blocks cell entry, has recently
been introduced into clinical practice.
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