Is it possible to defeat AIDS with the help of immunosuppression?
Alexander Hellemans, "In the World of Science" No. 3-2008
The human immunodeficiency virus (HIV) has a devastating effect on the infected person's body, disabling his immune system, which resists pathogenic microorganisms. As a result, a person is defenseless against any infection. What do doctors expect when they intend to defeat AIDS with the help of drugs that suppress the immune system?
Nevertheless, such therapy can become a new way to combat a deadly disease. Let's explain what's the matter here.
The main target of HIV are mature T-lymphocytes, known as helpers/inducers. They carry CD4 glycoprotein molecules on their surface, which recognizes the antigens of foreign agents. Activated CD4+1 T cells – the "conductors" of the immunological orchestra – not only produce cytokines in large quantities (chemicals that help organize a counterattack), but also enter the cell cycle, during which cell division and proliferation normally occur. However, in HIV infection, CD4+1-T cells probably undergo apoptosis during the cell cycle.
In addition, activated CD4+1 T cells somehow contribute to HIV replication.
(The figure shows HIV particles budding from an infected T cell.)
Scientists do not know exactly how the AIDS virus causes the activation of CD4+1-T cells and their mass destruction. They only know that a decrease in their concentration indicates the presence of a disease, and this indicator allows us to judge how far the pathological process has gone. It is also noted that if the activation of the immune system does not occur, then the picture does not look hopeless.
Experiments on monkeys can best clarify the situation. Mangobei living in West Africa have somehow adapted to the monkey immunodeficiency virus, other than HIV, and even with its high titer rarely get sick. However, Asian rhesus monkeys develop a syndrome similar to human AIDS when infected. The difference between the two primates is that in the former, the activation of the immune system during infection is insignificant, this limits the death of T cells and the replication of the virus. Rhesus monkeys have the same reaction to the virus as humans.
This observation prompted researchers to try to influence the human immune system so that it behaves like a mangobey. Experiments have shown that blocking virus replication with an anti-retroviral drug weakens the activation of the immune system and significantly increases the concentration of CD4+1-T cells. The next step could be immunosuppressive therapy, which should slow down the replication of the virus indirectly, by limiting the activation of T cells and preventing the mass death of CD4+1 T cells. Michael Lederman, director of the AIDS Research Center at Western Reserve University, reflects: "Perhaps by prescribing antiviral drugs to AIDS patients and blocking the subsequent pathways of T-cell transformation, we can accelerate the recovery of the CD4+1-T-cell population and return them to the true path."
A number of research groups from different countries are engaged in testing such an unusual approach. In 2001 and 2003, Liderman and his colleagues tested the effect of prednisone (corticosteroid hormone) in combination with antiviral drugs. The activation of the immune system was suppressed, but the increase in the concentration of CD4+1-T cells was not.
More success was achieved by a group from Europe using cyclosporine A. According to her supervisor Giuseppe Pantaleo from the University of Lausanne in Switzerland, trials involving first nine patients and then 80 showed an increase in the titer of CD4+1-T cells to normal levels after eight weeks of therapy. "The result just stunned us!" said Pantaleo.
This is really striking if we look at similar attempts made earlier. In 1989, a group from Canada also applied cyclosporine therapy, but without success. The patients showed symptoms of cyclosporine poisoning, nothing good happened with the concentration of T cells.
Apparently, the time factor is very important for such therapy. "It seems to me that treatment is useless if the disease has already passed into a chronic stage. If the infectious process has already started, then the mechanism of activation of the immune system becomes significantly more complicated," says Martin Markowitz from the Aron Diamond AIDS Research Center in New York. He hopes that the effect will be much better if you start acting at the earliest stages, when the virus is only detected, but the person is healthy. Markowitz prescribes small doses of cyclosporine to such patients for only four weeks. He proceeds from the fact that in previous tests, the increase in the concentration of CD4+1-T cells occurred too sharply.
The new strategy of attacking AIDS is just being tested for effectiveness, and the scientific community has not yet come to a consensus. But it should be borne in mind that with the spread of HIV resistance to antiretroviral drugs, immunosuppressive therapy may be the only tool in the fight against AIDS.
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14.03.2008