116
AIDS/HIV, Molecular and Cell Biology
and it is clear that glycosylation may
signifcantly inhibit the Function oF neu-
tralizing antibodies.
8
Vaccines
┬▒rom the above, it is clear that the de-
velopment oF a vaccine against HIV is
a monumental task compared to many
other pathogens. The Features that make
it particularly challenging are as Follows.
┬▒irstly, there is no evidence that complete
sterilizing immunity occurs in the hu-
man race aFter inFection. Thus, even the
best immune response in the world does
not appear to be capable oF indefnitely
checking virus replication. Secondly, the
huge variability oF the virus means that
unlike, For example, polio or smallpox,
vaccines containing a restricted number
oF variants will not successFully prevent in-
Fection and disease caused by HIV since
the virus has such a vast repertoire oF vi-
able variants. Thirdly, the virus integrates
into the genome oF the cell. A number oF
the Features oF the liFe cycle oF this and
other retroviruses have been designed to
specifcally maintain cellular viability since
death oF the cell equates with death oF the
provirus. The action oF many oF the ac-
cessory genes oF HIV in downmodulating
cell surFace proteins makes even a good im-
mune response incapable oF easily clearing
inFection. Over and above that, however,
the virus has the capacity to become latent.
Complete transcriptional arrest may occur
(or a level oF basal transcription insuFf-
cient to generate Tat), with transcriptional
reactivation occurring under appropriate
conditions such as triggering oF the cell
into mitosis. A transcriptionally inactive
virus is completely invisible to the im-
mune system and persistence oF a small
number oF latently inFected cells leaves
the possibility oF reactivation when the
immune response wanes. Reactivation oF
other viruses such as
Varicella zoster
pro-
vides a comparable parallel. It is, thus, not
surprising that progress toward a vaccine
has been slow. To date, vaccines have been
generated that are capable oF preventing
inFection in SIV models. Most oF these
appear to be eFFective against homologous
strains but with, as yet, relatively little evi-
dence that eFFective cross-neutralization oF
heterologous strains occurs. Use oF a live
attenuated vaccine such as one deleted in
nef
and some oF the other regulatory genes
has been associated with protection against
subsequent challenge. Attenuation, how-
ever, appears to be a fnite phenomenon
and mutation back to the wild-type se-
quence and Full pathogenicity is a Feature.
Recent data using prime boost techniques
in which carrier vaccine strains are used
such as modifed vaccinia Ankara have
shown some promising evidence oF good
immune responses against HIV proteins.
As yet, the duration oF immune response
using these techniques is not clear. A co-
hort oF prostitutes in western AFrica who
were repeatedly exposed to HIV but re-
mained uninFected originally, generated
hope that a Fully neutralizing immune
response was possible with Frequent low
level viral challenge. The Follow-up oF these
individuals showed that when sexual expo-
sure to HIV ceases, the immunity wanes
and the individuals become susceptible
to inFection again. This, again, is rather
a concerning issue in terms oF vaccine
development since it would suggest that
repeated boosts oF vaccination will be re-
quired to maintain a level oF immunity,
which would otherwise be lost. There
are strong parallels here with immunity
to malaria.
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