One might say, more so than ever, that the basic science
sessions at this year’s International AIDS Conference bring to the forefront the
importance for intensification of research efforts in understanding the immune system and
its role in both driving and controlling HIV replication.
Tuesday’s basic science sessions highlighted new
developments in research on :
- how the virus interacts with the immune system and;
- how it can destroy the capacity of the infected individual to respond to HIV.
Another major topic was the reservoir of infected cells left in
people who are receiving potent anti-HIV therapy. Emphasis was placed on CD4+ T cells that
remain in the immune tissue (i.e. lymph nodes) and may hold the virus silent or leave it
producing low levels of virus.
Tuesday presentations on how certain normal immune responses may
have a major impact on HIV replication heralded the theme noted above - the immune system,
its defects and normal responses as a consequence of infection, is a critical force in HIV
disease progression. The following is a summary of major themes presented and further
elucidated.
- It has been well established that shortly after initial HIV infection, hours to
days, the virus establishes itself in resting CD4+ T cells. One way that researchers can
look at CD4+ cells is by examining the percentage which are resting compared to those
which are active.
A resting T cell becomes activated when it needs to function, such as respond to
an infection. When a CD4+ cell is activated, it becomes a target for HIV infection. The
majority of cells that become infected are destroyed by the infection. Some percentage of
cells, however, return to a quiet, resting state.
The infected resting T cell becomes a reservoir for HIV. Nearly all of the
currently available anti-HIV drugs do not affect the virus unless it is in an active
state. Moreover, when the virus is lying dormant in resting cells it is hidden from the
immune system.
Thus, virus in these resting cells is capable of rekindling the fires of HIV
infection and represents a threat to long-term and continued control of HIV with the
currently available anti-HIV therapies.
- A number of factors have been shown to increase HIV replication, cytokines, for
example. Cytokines are naturally occurring immune chemicals that can be likened to the
language of the immune system. Cells produce various cytokines as a means to communicate
with one another, such as to initiate immune responses against infections.
Certain cytokines, IL-1 beta, TNF-alpha and IL-6, have been shown to increase
HIV replication. Studies have shown that therapy with a triple-drug protease inhibitor
containing regimen decreases levels of some of these cytokines and also decreases HIV
levels.
Even in settings where HIV has been maximally suppressed, to below the limit of
detection on sensitive tests, for long periods of time, there is typically a rebound in
measurable virus when therapy is stopped.
This virus is presumably coming from HIV infected resting cells that are driven
by cytokines released from activated cells.
- Another way that cytokines (e.g. IL-4) can affect HIV is by affecting co-receptor
expression. In Monday’s summary, we discussed the role of CXCR4 and CCR5. One study
showed that IL-4, in a test tube, increased CXCR4 on cells and reduced CCR5 on cells. This
may lead to an increase in the HIV type (i.e. SI) which utilizes CXCR4 for cell entry, and
these types of virus are more aggressive.
- Given that current therapies cannot attack this reservoir for HIV infection,
approaches that enhance the ability of the immune system to control HIV are critical.
Another potential solution to this problem, however, may be to purge the reservoir, either
by destroying the cells with immune ablative techniques, or by aggressively activating
these quiet cells in order to make the virus in them visible to anti-HIV drugs as well as
the immune response. Some of these approaches are currently being tested in studies.
- One presentation highlighted information on the rate of viral decreases from a
small number of people who received triple-drug therapy. The test used to measure HIV
levels looked for virus inside of cells. The rate at which cell-associated virus decreased
was highly variable between the patients.
Despite HIV levels falling below the limit of detection of the currently
available tests, cell-associated virus was detectable in all study participants.
Discouraging was news that when examining the virus from volunteers at different
time points, it was increasingly changing and mutating. This finding suggests that despite
potent anti-HIV therapy, at some low level there is ongoing HIV replication.
Fortunately, however, at least in those people studied, the mutating virus was
not apparently developing resistance to the drugs. These findings were also observed in
people recently infected by HIV who received anti-HIV therapy shortly after infection.
- In addition to the direct infection and destruction of CD4+ T cells by HIV, other
processes may be at work accounting for CD4+ T cell decline throughout the course of HIV
disease.
Not only are CD4+ T cells being destroyed by HIV infection, but also there
appears to be other processes, such as a defect in the production of new immune cells.
This defect may be at the level of the bone marrow, the environment from which
all white blood cells are derived. HIV could interfere with a cell’s ability to go
down its path of maturing. Also, HIV could infect the thymus, the key organ necessary for
new T cell development.
Further exploration of these theories is important, and if correct could lead to
new directions in research for HIV therapies.
Other notable new developments include :
- Large numbers of groups have used DNA-based vaccine approaches in HIV uninfected
people and in animals. Others have combined this approach with the use of vaccines
employing the canarypox virus carrying an HIV protein.
The anti-HIV immune responses to these novel vaccine approaches have been noted,
including antibody responses and in some cases cellular responses.
In one study cellular responses generated appeared to be effective against
strains of viruses found in diverse parts of the world (i.e. across clades).
- In Monday’s summary we discussed the role of chemokines and chemokine
receptors in HIV infection. Studies presented on Tuesday indicated that chemokines can
increase or decrease HIV replication depending on the amount of chemokine to which the
cells are exposed.
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