HIV appears to wear out the immune system. Killer T cells that would typically proliferate to ward off an infection instead languish under the HIV onslaught. Two independent teams of researchers have uncovered the cause of this failure, tracing it to a particular molecular pathway known as Programmed Death-1, or PD-1.

Earlier research by Rafi Ahmed of Emory University found that such viral infections in mice stall the innate immune response by flicking on the PD-1 switch, which keeps the T cells from functioning. Furthermore, by blocking that switch, his team could restore the T cells to the fight and reduce the amount of virus in the infected mice. Such findings inspired Bruce Walker of Harvard Medical School and his team to investigate the PD-1 pathway in humans.

The researchers focused on untreated individuals in Durban, South Africa, an area in the grips of an AIDS crisis where more than 30 percent of its population--and 50 percent of pregnant women--are infected. They found that the immune cells of 71 HIV-infected subjects had elevated levels of PD-1 expression compared to uninfected controls. The afflicted cells proved unable to function in the presence of HIV and thus the subjects had higher overall levels of the virus. "It's long been known that people with HIV infection have a lot of HIV-specific immune cells that one would think would be actively combating the virus," Walker says. "But a major puzzle has been that even in late stage illness, when one can still measure great numbers of these immune cells, they don't seem to be controlling the virus at all." A research team led by Rafick-Pierre Sekaly of the University of Montreal found similar correlations in a paper published yesterday in Nature Medicine.

Blood samples from four patients taken both before and after they began antiretroviral therapy revealed that PD-1 expression dropped in the wake of treatment in the Walker study. And by actively blocking the PD-1 pathway the researchers were able to boost the numbers of HIV-fighting immune cells in the samples. "We wanted to determine whether these T cells had been irreparably damaged or misprogrammed," Walker explains. "And we found that they are capable of functioning, they've just been turned off."

"The majority of patients we have studied had no detectable levels of these HIV-specific cells, but as soon as we blocked the PD-1 pathway, they had a ton of them," he continues. This does not mean, however, that a new treatment for AIDS is at hand, the authors warn in the paper presenting the finding, which was published online by Nature yesterday. Although drugs to block the PD-1 pathway have been developed for cancer patients, they affect all immune cells, not just HIV-specific ones. "If you turn back on an immune regulatory switch that the body has decided to turn off," Walker cautions, "you could trigger serious immunological problems."