Rafi Ahmed and his colleagues believe that a boost to the immune system, combined with drugs, could give viruses a one-two punch that could keep them at bay for years.

EMORY (US)—Recent experiments in monkeys suggest blocking a key trigger of immune “exhaustion” could help revive humans’ ability to fight chronic infections such as hepatitis C or HIV/AIDS.

Researchers have long dreamed of finding a way to revive the immune system after it has been worn out by a chronic infection. The antiretroviral drugs that emerged in the 1990s can make HIV infection a more manageable condition, but they are expensive and must be taken for the rest of the patient’s life. Similarly, the lifetime cost of hepatitis C treatment is estimated at more than $100,000.

Scientists at the Emory Vaccine Center and Emory University’s Yerkes National Primate Research Center now believe that a boost to the immune system, combined with drugs, could give viruses a one-two punch that could keep them at bay for years.

Recent results reported in Nature suggest an attractive target for therapy: the molecule PD-1, which ordinarily dampens immune responses during chronic infections. Treating monkeys infected by HIV’s cousin SIV with an antibody against PD-1 allowed them to fend off the virus for several months.

Vaccine Center Director Rafi Ahmed and his colleagues were the first to discern PD-1’s role in chronic infections in a mouse model. PD-1’s levels rise on T cells as a mouse’s immune system fights a chronic infection. Several laboratories have confirmed that the same is true of T cells in humans suffering from several chronic infections, such as HIV, hepatitis C and tuberculosis.

PD-1 appears to have the job of keeping immune responses from getting out of control. Without it, mice develop autoimmune diseases: lupus or a weakened heart, depending on the strain. Part of a complex network of regulatory molecules, it inhibits T cells’ ability to recognize foreign invaders and respond to them.

Ahmed says viruses involved in chronic infections are taking advantage of limits imposed by molecules like PD-1. Viruses such as HIV can wait for T cells and other immune cells to become “exhausted”, and then establish themselves for the long term. After enough time goes by, the T cells act like the viruses are part of the body and don’t attack.

“It’s sort of like they’re hypnotized,” he says. “They don’t see the enemy.”

Because blocking PD-1 takes the blinders off, one of the main risks doctors see from such therapies is the possible side effect of autoimmunity.

For this reason, researchers are envisioning a brief period of immune system therapy that will be “short and sweet.” Yerkes immunologist Rama Rao Amara is already planning what he calls “the ideal experiment.”

Working again with SIV-infected monkeys, he plans to combine the PD-1 antibody treatment with antiretroviral drugs, either simultaneously or in tandem, to determine what works best. While the results from SIV-infected monkeys were promising, similar immune-stimulating therapies have grabbed attention over the years, only to fade away after rigorous clinical tests.

A potential trap lies in the way HIV ensnares the immune system. HIV specifically targets CD4+ or “helper” T cells, the white blood cells that direct much of the rest of the immune system.

“If you do something to make CD4 T cells more healthy, you could give the rest of the immune system more help, but you could also be giving the virus more targets,” Amara says.

Blocking PD-1 may turn out to be a more balanced approach, because doing so stimulates more than one arm of the immune system, Amara says.

At the same time, Ahmed and a team of laboratories from several universities are expanding their study of the basic biology of PD-1 and beginning tests on monkeys infected with hepatitis C. Even considering the work ahead, PD-1’s future looks bright.

Ahmed’s PD-1 research is supported by the National Institutes of Health, the Gates Foundation and the Concerned Parents for AIDS Research.

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