AIDS/HIV, Molecular and Cell Biology
115
Structured treatment interruptions (STI)
is being tested as a strategy to reduce drug
toxicity. As yet, the effect of this on overall
prognosis and immune regeneration is not
fully established.
7
Viral Escape
The previously described inFdelity of the
reverse transcriptase enzyme is responsi-
ble for considerable sequence change in
the virus. Undoubtedly, many of the incor-
porated nucleotides will cause lethal muta-
tions and a nonviable integrated provirus
will result. The huge numbers of viruses
being produced everyday, however, will en-
sure that a large number of viable variants
will be produced, which may have mi-
nor changes in their amino acid sequence.
Thus, it is easy to see that a virus en-
tering a macrophage may mutate slightly
during its reverse transcription and in-
tegration process such that the progeny
virions from that cell may have a slightly
greater predisposition to infect lympho-
cytes than the parental version. The other
major mechanism of sequence variation
comes from recombination. When a cell
is infected with two different viruses, the
diploid nature of the genome means that
it is possible for an RNA strand from
two different integrated proviruses to be
copackaged. During reverse transcription
in the target cell, the reverse transcrip-
tase enzyme is known to dissociate from
its template and may reassociate with the
partner template. Thus, exchange of large
blocks of genetic information between the
two strands is quite common. Indeed, it is
estimated that the enzyme skips between
strands at least four times during every
replication cycle. In this way, mixing and
matching of genomes can occur with ease
and, in this case, large blocks of func-
tionally intact genome will be changed.
Recombination is, therefore, believed to
be as signiFcant if not more signiFcant
than RT errors in generating diversity.
Some of the major worldwide clades have
clearly been formed from recombination.
Genotype E in Thailand, for example, is a
recombinant between a clade A Gag and a
clade E envelope sequence.
Variation allows the virus to introduce
point mutations, which will render the
binding of antiviral drugs much less ef-
Fcient, and strategies to combat viral
resistance have become an integral part of
clinical management. This is particularly
the case since antiviral therapy in the west-
ern world became more widespread. The
chances of acquiring a virus, which has al-
ready generated some antiviral resistance,
has increased greatly. ┬▒or this reason,
where possible, it is recommended that
antiviral resistance testing is undertaken
before initiating antiretroviral therapy so
that the combination of drugs chosen is
one in which the virus is sensitive to
each component. As well as this, it is
vital that combinations of three or more
drugs are used to prevent emergence of
resistance. Both of these strategies are de-
signed to avoid presenting the virus with
a single drug against which it can de-
velop resistance.
The genetic variation also contributes
very largely to the difFculty the immune
system has in neutralizing this virus.
There are clearly documented examples
of immunological escape where viral pro-
teins, which have cytotoxic T-cell epitopes,
mutate and thus escape cytotoxic T-cell
recognition. In terms of envelope varia-
tion, the virus has the additional weapon
of variable glycosylation. HIV envelope is
extremely heavily glycosylated compared
to a number of its close viral relatives
previous page 115 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 117 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off