trans

108 ANTIGENIC VARIATION
silenced. Each maturing parasite transcribes
only one var gene, whose choice is independent
of chromosomal location. There is no evidence
for gene conversion or any other rearrangements
associated with var switching, and the
regulatory mechanisms are unknown. On the
other hand, telomere clustering has been shown
to lead to higher rates of recombination
among telomeric var genes than would be
expected at chromosome-internal loci. Thus,
even if not involved in regulating expression,
telomeric loci can be a major contributor to
the generation of var diversity. This is a topic
that has yet to be explored in trypanosomes.
As with the regulation of VSG expression, the
study of var genes promises to make an interesting
contribution to the general topic of
epigenetic regulation.
MEDICAL APPLICATIONS
The prospects for vaccination against African
trypanosomiasis appear slim, based on the role
of antigenic variation and the discouraging
results of early vaccine studies. There has been
almost no follow-up of alternative vaccine
possibilities in the last two decades, although
there are concepts that have been around for a
long time. One idea is that, although responses
to VSG dominate the immune system, an
immune response to invariant or less variant
proteins could be effective if induced by strongly
immunogenic antigen preparations prior to
exposure to VSG. Another idea concerns the
possibility of targeting vaccines to proteins that
are confined to the flagellar pocket. Serum proteins
must be able to enter this compartment,
where the transferrin receptor resides. Finally,
there have been suggestions that the potential
for antigenic variation in T. gambiense might be
more limited than in T. brucei or T. rhodesiense,
so VSG-based immunoprotection might be a
testable, if unlikely, option. On the negative
side, however, is the ominous thought that trypanosomes
have been around for a long time,
and they may understand our immune system
better than we do. However, some of these ideas
merit further exploration, especially since
T. brucei has many proteins with a predicted cell
surface location, and the genome sequence
will allow many more candidates to be identified.
Some of these surface components could
be investigated empirically, as potential
vaccines.
In the early 1980s, there was widespread optimism
that malaria vaccines would soon be
developed. However, the potential for antigenic
variation now seems as great for malaria parasites
as for trypanosomes, which is discouraging
for the development of vaccines against the
bloodstream stage. There are additional issues
that have to be considered, beyond the implications
of the molecular mechanisms for antigenic
variation, when assessing the possibilities
for malaria vaccine development. Although any
vaccine would be very unlikely to provide sterile
immunity, a vaccine that would reduce the level
of erythrocyte infection in early childhood but
allow broader immunity to develop through the
boosting effect of continuing natural challenge
would be a major life-saver in malaria-endemic
areas. Discussion of immunization possibilities
against other stages of the malaria life cycle is
beyond the scope of the present focus on antigenic
variation. Perhaps what we need more
than any vaccine is a range of cheap, safe and
effective drugs for malaria and for trypanosomiasis.
There is no shortage of novel targets for
anti-parasite drugs and it is inconceivable that
such drugs could not be readily identified.
Unfortunately, there is no economic incentive
and little effective public support, in the wealthy
regions of the world, for the development of
drugs to treat tropical parasitic diseases.
MOLECULAR BIOLOGY