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HIV
vaccine development—
The
hurdles faced by scientists
The
reasons why we still do not have a vaccine to stop the spread
of HIV are complex and varied, and go beyond the scientific
hurdles. But these obstacles are themselves immense.
Effective vaccines for some infectious diseases work because
they present the immune system with antigens to which antibodies
are produced. However, many researchers do not believe that
merely inducing antibodies against HIV would prevent the virus
from establishing an infection.
Such
pessimism for an antibody-based approach stems in part from
what has been learned about the role of antibodies against
HIV on the natural course of an infection. Within weeks of
HIV infection, the amount of virus in the blood (viral load)
reaches extremely high levels. Several weeks later, the viral
load falls dramatically to a much lower level. Only after
this reduction has occurred do antibodies that effectively
neutralize HIV appear in the blood. This suggests that some
other kind of immune reaction is responsible for the initial
control of viral load. Furthermore, neutralizing antibodies
in the blood of infected individuals do not seem to greatly
influence the subsequent course of infection (i.e., the length
of time before CD4 counts fall and AIDS-defining symptoms
are seen in the absence of treatment).
Finding correlates of protection
If neutralizing antibodies will not do the trick, some other
immune response must be employed. A wide spectrum of possible
antiviral responses are available to the immune system, and
scientists have been attempting to correlate them with protection
against HIV infection in animal models. Unfortunately, in
part because these responses can be difficult or impossible
to measure, these so-called "correlates of protection" are
still undefined.
For example, antibodies produced at mucosal surfaces—as
opposed to antibodies circulating in the blood—may have
more impact on HIV transmission, because the majority of new
infections occur at the mucous-coated surfaces of the uro-genital
tract and the gastrointestinal tract. Much work has been going
into the development of a "mucosal" HIV vaccine, but since
there is little precedence in vaccinology for such approaches,
researchers still lack basic information about them.
Many
scientists believe that the dramatic albeit incomplete immune
control of HIV seen shortly after infection (as discussed
above) is due to the activity of CD8 cells, sometimes referred
to as CTLs (though the terms are not synonymous). Could CD8
cellular activity represent a necessary correlate of protection?
CD8 cells in fact perform a number of antiviral activities,
but whether these cells can sufficiently protect against infection
remains an open question. Still, researchers have been paying
greater attention to the effects of HIV vaccine candidates
on CD8 cell functioning.
Other
immune responses might also have an impact on HIV infection.
Many kinds of immune cells secrete chemicals into the blood
that strongly affect the response to microbial infections.
One such class of chemical, called chemokines, has
been associated with protection in animal models of HIV vaccine
candidates.
HIV vaccine development suffers from an incomplete understanding
of how these various immune responses can impact HIV transmission.
HIV
diversity yet another hurdle
The global epidemic involves not a single virus, but a genetically
diverse family of HIV. It remains unknown how this will impact
vaccine development. The predominant type, or "clade", of
virus in North America and Europe is clade B, but in many
Third World countries, non-B clades predominate. Clade C,
in fact, now is responsible for the majority of new infections.
For this reason, some scientists have been calling for a greater
allocation of resources towards the development of a vaccine
appropriate for protecting against transmission of clade C
virus.
Can an HIV vaccine be developed that protects against multiple
clades of virus? Some experimental vaccine candidates are
capable of inducing immune responses effective against HIV
of several clades—so called "cross-clade" protection.
But without knowing what constitutes the correlates of protection
against HIV infection, one cannot be certain in advance how
cross-clade protection can be achieved in practice.
Attacking
the immunosuppression
The entire problem can be viewed at another level. What if
there are immune responses that could protect against infection,
but HIV prevents them from being activated? Even within the
first years of the epidemic, it was becoming clear that the
impairment of the immune system can be out of proportion to
the loss of immune cells. Immunosuppression by HIV is not
just a matter of how many cells it kills, it seems.
Data
have been accumulating to suggest that the HIV protein Tat
is a toxin that is at least partially responsible for this
immunosuppression. In infected individuals, Tat can be found
dissolved in the blood, independent of the virus. Though probably
still a minority view amongst researchers, it has been suggested
on this basis that Tat will be a necessary component of a
preventative HIV vaccine. The argument (still controversial)
is that the long-sought immune correlate of protection against
HIV is inhibited by Tat. If so, then a Tat vaccine might permit
these responses to emerge. The vaccines against several infectious
diseases actually do consist of inactivated toxins produced
by the microbes, so that this approach has some precedence.
Prospects
The very nature of HIV infection requires new thinking about
vaccine approaches. HIV presents issues that have not necessarily
been encountered before with other diseases. They will have
to be resolved by focused and continued effort.
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