Geneva,
SWITZERLAND (6/30/98)- New biological tools for enhancing the immune
system's defense against stray HIV cells may complete the job of eliminating
the AIDS virus started by powerful antiretroviral combination therapies,
according to new studies presented at the 12th World AIDS Conference.
With the right chemical cocktail of antiretroviral drugs, it is now
possible to reduce HIV blood levels almost completely, keeping HIV infection
in check and slowing or preventing the development of AIDS. But some HIV
remains hidden in various parts of the immune system. Even a couple of
viral particles can reinfect T-cells and start the whole disease process
over again. Researchers are looking at a number of ways of boosting the
immune system's tools for dealing with these stray pathogens.
Scientists at the University of Pittsburgh Graduate School of Public
Health believe that boosting the virus-killing capability of a small group
of immune cells, CD8 T cells, also referred to as killer T cells, may be
the key to establishing long-term immunity against HIV-1. The researchers
presented the first evidence that even small numbers of killer T cells
present in late-stage AIDS patients after extensive antiretroviral chemotherapy
can be activated against HIV-1.
The researchers were able to accomplish this anti-HIV-1 effect by treating
another group of immune cells called dendritic cells with HIV-1 proteins
and interleukin-12. When dendritic cells are exposed to HIV proteins, they
"study" the viral structure and teach other immune cells to identify any
cell infected with these HIV-1 proteins. While the dendritic cells are
inspecting the proteins, they release substances like IL-12, which stimulate
immune cells to multiply and attack foreign objects.
"This indicates that we may be able to enhance the body's response to
the virus, which is very exciting because it suggests that with some prodding
and priming, we may be able to train the immune system to ward off further
attacks by HIV," said Dr. Charles Rinaldo, Ph.D., chairman of the department
of infectious diseases and microbiology at the University of Pittsburgh.
Boosting the patient's immunity to HIV in this way might eventually
allow discontinuation of the complex regimens of drugs required for treatment
of HIV infection. Treatment can involve taking 18 pills a day, along with
careful monitoring of which drug is taken when and under what conditions.
Dr. Rinaldo's research team was the first to find that the triple therapy
regimen of a protease inhibitor (indinavir) with two nucleoside reverse
transcriptase inhibitors (zidovudine and lamivudine) allowed a group of
killer T cells, sometimes called memory CD8 T cells, to increase dramatically
two to three months after initiating treatment. These CD8 T cell levels
remained high for about a year. Despite the small amount of killer T cells,
levels of freely circulating virus in these patients remained so low they
weren't detected with a commonly used test known as viral load.
"We're not quite sure why we see the rise in memory CD8 T cells. But,
we think that when the virus is suppressed, these immune cells are able
to grow freely, without any inhibition. This may help to explain the immediate
rise in the number of memory CD8 T cells," he said.
Low levels of killer T cells have also been observed in so-called 'long-term
non progressors,' HIV-infected individuals who have maintained unusually
low levels of the virus for a very long time, with no evidence of disease.
This could indicate that the body is adjusting to some sort of normal state,
he added.
The crucial question is whether the small numbers of memory killer T
cells and their precursors, naive CD8 T cells, are capable of mounting
a strong response against HIV. The Pitt researchers conducted a study in
which dendritic cells were taken from three HIV-infected study participants,
stimulated with IL-12 and exposed to HIV-1 proteins encapsulated in a liposome,
a tiny, fatty structure often used to deliver genes and other materials
safely to the inside of a cell. The researchers found that dendrtic cells
"pulsed" two to four times in laboratory dishes with the HIV-1 proteins
and IL-12 were able to teach the killer T cells to recognize three important
viral markers in HIV-infected cells. Recognizing these viral markers enables
killer T cells to identify, attack and kill cells infected with HIV-1.
"We were encouraged to see that the killer T cells were ready, alert
and could attack HIV-infected cells after the dendritic cells gave them
the signal. By further stimulating naive T cells or boosting residual memory
T cells with therapeutic vaccines similar to the one we used in this study,
it may be possible to achieve complete immunity in patients. This
would then allow a patient's immune system to exert a much stronger control
over HIV-1 infection," said Dr. Rinaldo.
Boosting Macrophages: New Immune Approach
Encouraging macrophages to fight infections and restore immune system
function may provide another way to eliminate small amounts of HIV from
the system following drug treatment, report researchers at the University
of California, San Francisco.
Macrophages are a kind of white blood cell that "eat" invading bacteria
and viruses and help lymphocytes function. But diseases, such as AIDS,
can render macrophages ineffective. The UCSF researchers reported that
a new compound called WF10 (tetrachlorodecaoxygen) boosts macrophage activity.
"In late-stage AIDS, macrophages are the body's last line of defense
in the weakened immune system. Our
studies suggest that WF10 can stimulate macrophage function without
changing the AIDS virus load," said Brian Herndier, Ph.D., M.D., associate
professor, Department of Pathology, University of California, San Francisco.
"One of the greatest shortcomings of existing AIDS drugs is that over
time, or with poor compliance, the virus becomes resistant to even anti-retroviral
"cocktail" therapy in the blood plasma," said Michael McGrath, M.D., Ph.D.,
professor, Department of Laboratory Medicine, University of California,
San Francisco. "While we continue to look at ways to kill the virus, the
next promising treatment is one that directly targets the reservoir of
the virus and reoccurrence of the virus that impairs the immune system.
Advanced laboratory studies show that WF10 increases the healthy activity
of macrophages, thereby reconstituting an important defense mechanism.
The most exciting piece of this preliminary clinical research is that WF10
activation of macrophages may encourage the immune system to better fight
AIDS and opportunistic infections."
The studies also showed that WF10 decreased the blood levels of CD38,
a marker that is a possible predictor of AIDS progression, and increased
the blood levels of CD8 cells, an important T-lymphocyte that helps combat
the virus. In addition, the studies showed that WF10 did not increase the
amount of HIV in the blood or cause reoccurrence of resistant strains of
the virus, one of the major disadvantages of immune stimulation.
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