Just showing up might be 90 percent of success for Woody Allen, as he once claimed. But in HIV cells, killer T cells that follow the same approach do more harm than good.

"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," said Bruce Walker, professor of medicine at Harvard Medical School. "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."

Even worse, the immune system, apparently unaware that its AIDS soldiers have been reduced to observers, does nothing to prod them to action or replace them with more competent fighters.

Two papers in Nature and Nature Medicine, respectively, describe the molecular mechanism that shuts off T cells in late-stage HIV and show in vitro data suggesting that in principle, those T cells could be reactivated.

HIV is not the only chronic infection that leaves the immune system unable to completely clear a virus. Recent animal studies showed that in several chronic viral infections, T cells are actively inhibited via the PD-1 pathway.

That pathway already is being targeted to boost the immune system in a different indication. Earlier this month, Medarex Inc., of Princeton, N.J., and Ono Pharmaceutical Co. Ltd., of Osaka, Japan, announced that the FDA granted their investigational new drug application for a fully human anti-PD-1 antibody in the cancer arena.

In the new papers on PD-1's comings and goings in HIV patients, the authors found that PD-1 expression was higher on HIV-specific killer T cells than on either T cells aimed at other viral infections or T cells from uninfected controls.

Helper T cells also showed high levels of PD-1 expression. Increased PD-1 expression on killer T cells correlated with increased viral load and reduced levels of helper T cells, both of which are predictors of HIV progression.

In vitro, blocking the PD-1 pathway in blood cells from infected individuals enabled HIV-specific killer T cells to proliferate and secrete antiviral cytokines. Blocking the PD-1 pathway also increased the proliferation of HIV-specific helper T cells. Previously inactive T cells could be turned on again by blocking the PD-1 pathway.

The subjects in the Nature paper were South African individuals who had not begun antiretroviral treatment. When the scientists compared PD-1 expression in some of their patients before and after the onset of antiretroviral therapy, they found a significant decrease in PD-1 expression on HIV-specific T cells.

Why the immune system essentially shoots itself in the foot by turning off its T cells in some chronic viral infections is not known, but Walker, who is the senior author of the Nature study, told BioWorld Today that "obviously, the immune system has to have a way to turn itself on and turn itself back off," adding that perhaps in the case of viral infections, that all-clear signal simply comes too early.

The Nature study was reported by scientists from the University of KwaZulu Natal in Durban, South Africa; Harvard Medical School in Boston; Oxford University in the UK; Emory University School of Medicine in Atlanta; the Wistar Institute in Philadelphia; and the Howard Hughes Medical Institute in Chevy Chase, Md.

The Nature Medicine co-authors are from the University of Montreal and McGill University, also in Montreal; the Blood Systems Research Institute in San Francisco; and BD Biosciences in San Diego.