A caution light for AIDS
by Quinn Eastman
Can suppressing a little molecule known as PD-1 slow HIV from going to full-blown AIDS?
Andrew Lipschitz was one of the first doctors to become infected with HIV through a needle stick. In the early 1990s, he nearly died of AIDS-related lymphoma. Although relatively healthy now, he takes seven drugs every day to stave off HIV, a regimen that costs thousands of dollars a year. Lipschitz knows firsthand that a treatment that would allow someone living with the virus to go off medication for long periods of time would be extremely valuable. He's helping support just such an effort as medical director of Concerned Parents for AIDS Research, a New York-based charity organized by parents who have all been touched by AIDS.
Last year, the group contributed $250,000 to the Emory Vaccine Center, a seed grant that supported collaboration between the lab of Georgia Research Alliance Eminent Scholar Rafi Ahmed, who directs the center, and researchers at Harvard. That work has blossomed into a $13 million NIH-funded collaboration among several universities aimed at understanding how the immune system is tricked by chronic infections such as HIV/AIDS and hepatitis C.
A green light for balanced immunity
The researchers believe that a boost to the immune system, combined with medication, could send a strong holding signal to HIV for years.
In December 2008 in Nature, they described what appears to be an attractive target for HIV therapy: the molecule known as programmed death-1. PD-1 is an immune system receptor that is able to hamper immune responses during chronic infections. Treating monkeys infected by HIV's cousin, SIV, with an antibody against PD-1 allowed the animals to fend off the virus for several months.
"I didn't think that the results from primates would be so strong," says Rama Amara, an Emory researcher at the Yerkes National Primate Research Center who works with Ahmed and performed the monkey studies. "They really blew me away."
A potential clue as to why these results were so strong lies in the way HIV attacks the immune system, Amara says. HIV attaches to CD4+ or "helper" T cells, the white blood cells that initiate the body's response to invading micro-organisms.
Previous experimental therapies focused on raising the levels of CD4+ T cells in infected people because patients appear to become more vulnerable to opportunistic infections when levels of the cells drop. But there's a catch. "If you do something to make CD4+ T cells healthier, you could also be giving the virus more targets," says Amara.
Blocking PD-1 may turn out to be a more balanced approach because PD-1 dampens more than one arm of the immune system, Amara says. In SIV-infected monkeys, blocking PD-1 did temporarily increase levels of the target CD4+ cells and HIV in the blood. But antibody-producing B cells and "killer" T cells (which clear virus-infected cells from the body) then pushed HIV levels down in a sustained way for months in some animals.
"We're finding that having enough antibodies to resist other opportunistic infections plays an important role in preventing viral infection from progressing to full AIDS," he says.
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Rama Amara was surprised at how well monkeys were able to fend off AIDS with the help of an antibody against the molecule known as PD-1.Treating monkeys infected by HIV's cousin, SIV, with an antibody against
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A red light for autoimmunity
PD-1 apparently plays a role in keeping immune responses from getting out of control. Part of a complex network of regulatory molecules, PD-1 inhibits the ability of T cells to recognize foreign invaders and respond to them. Without PD-1's constraints, the immune system tends toward autoimmunity, with antibodies attacking the body's own tissues indiscriminately.
Mice genetically engineered to lack PD-1 tend to develop either a lupus-like condition or a weakened heart. In people, variations in the gene have been linked with autoimmune diseases such as lupus, rheumatoid arthritis, and type I diabetes.
Ahmed and his colleagues were the first to discern the role of PD-1 in chronic infections. They compared T cells from mice infected with two strains of an encephalitis-causing virus. One strain causes an acute infection that eventually clears, while the other causes a long-lasting infection.
Levels of PD-1 rise in T cells as the immune system fights a chronic infection. Ahmed says that viruses involved in chronic conditions are taking advantage of limits imposed by molecules like PD-1. Viruses such as HIV and hepatitis C 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 as if the viruses are no longer threats and cease their attack.
"It's as if they're hypnotized," he says. "They don't see the enemy."
Driving change agents
With an eye to minimizing side effects as well as keeping costs low, Amara envisions a "short and sweet" period of immune system therapy. Working with SIV-infected monkeys, he is combining PD-1 antibody treatments with antiretroviral drugs, either simultaneously or in tandem, to determine what works best.
With the new federal funding, Ahmed is steering a broad effort to explore PD-1 biology that includes scientists from Emory, Harvard, New York University, and the universities of Montreal and Pennsylvania. The NIH support will enable them to explore several questions. Which is the most important molecule to partner with PD-1 when developing therapies? How is the PD-1 gene turned on and off? How do different pairings of PD-1 with other molecules relate to its ability to withstand HIV's onslaught for an extended period?
Because PD-1 has a common role in the response to several chronic infections, blocking it could help shape therapies for not only HIV but also hepatitis B and C. Already a study in chimps at Children's Hospital in Columbus, Ohio, is testing whether blocking PD-1 could work against hepatitis C. In addition, an independent biotechnology firm is examining PD-1 antibodies as a potential therapy for advanced forms of cancer.
Meanwhile, Lipschitz finds it satisfying to see how far the seed money from Concerned Parents has grown into a powerful potential signal to control HIV.
