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See Inside December 2007

T Cell Turnoff

Can suppressing the immune system treat HIV infection?

HIV is devastating because it attacks and destroys the body’s defense system against pathogens, leaving patients fatally exposed. So what would possess scientists to treat HIV-positive patients with drugs that suppress the immune system?

Such therapy may in fact offer a new approach in the battle against AIDS. An unexpected feature of HIV infection is that in the first few weeks after invasion, the virus hijacks the immune system and sends it into overdrive. Most significantly, the activated T cells—the soldiers that fight germs—not only produce large amounts of cytokines (chemical messengers that help to coordinate a counterattack) but also enter the cell cycle, a process that normally leads to cell division and proliferation. In HIV infection, however, a T cell subtype called the central memory CD4+ T cell appears to enter the cell cycle and undergo apoptosis—cellular suicide—in vast numbers. The activated CD4+ T cell population also helps the virus replicate.

Scientists are not exactly sure how HIV causes the CD4+ T cell population to activate and crash. They do know that the decline is characteristic of HIV infection and use it to make prognoses. They also know that if immune activation is absent, the outlook is very different.
Nowhere is this clearer than in the laboratory with monkeys. The sooty manga­bey, found in West Africa, has somehow adapted to the simian immunodeficiency virus—the nonhuman version of HIV—so that even with a high viral load, it rarely gets sick. In contrast, the Asian rhesus macaque will commonly develop a syndrome resembling AIDS. The difference between these two primates is that the sooty man­gabey experiences only low levels of immune activation, which presumably limits the T cell population crash and viral replication. In contrast, the rhesus macaque’s immune system, like that of humans, is highly activated in the early stages of infection.

This correlation led researchers to wonder what might happen if the human immune system behaved more like the manga­bey’s when confronted by the virus. Experiments have already established that blocking viral replication with antiretroviral medication attenuates immune activation and boosts the number of CD4+ T cells. The next step would be immunosuppressive therapy, which could slow down viral replication by limiting the T cell activation and prevent the CD4+ T cells from committing suicide. “Maybe if we gave antiviral medications and blocked the downstream pathways that are driving T cell turnover, we might be able to enhance CD4+ T cell restoration and T cell function,” says Michael Lederman, director of the Center for AIDS Research at Case Western Reserve University.

Several teams around the world have been investigating this unusual approach, with mixed results. Lederman and his colleagues conducted trials in 2001 and 2003 of the corticosteroid prednisone in conjunction with antiretroviral therapy. The therapy succeeded in blocking immune activation but failed to affect CD4+ T cell populations.

A European team fared better with cyclosporine A. In a nine-patient trial—and later, in a study of nearly 80 patients—CD4+ T cell counts rose to normal levels after eight weeks of cyclosporine A and antiretroviral therapy, says immunologist Giuseppe Pantaleo of the University of Lausanne in Switzerland, a key investigator in the trials. “We were indeed surprised by the magnitude of the effect on the CD4+ T cells,” he remarks.

Pantaleo’s results stand in stark contrast to some previous attempts. In 1989 Canadian researchers attempted to treat patients with AIDS using cyclosporine, with unfortunate consequences. Not only did patients experience severe toxic symptoms from the treatment, but their T cell counts plummeted.

Hence, timing seems to be important with this kind of HIV therapy. “This is not, in my mind, an approach to take during chronic infection, because once infection has been established, the mechanisms of immune activation become much more complicated,” observes Martin Mar­kowitz, staff investigator at the Aaron Diamond AIDS Research Center in New York City. “I don’t think that you want to intervene in a disease that is characterized by progressive immunosuppression with immunosuppression.”

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