August 24, 2006

T-Cell Protein May Be HIV Treatment Opportunity

August 24, 2006 (AIDSmeds)—Researchers have reported what they see as an important breakthrough in fighting HIV. They have identified and confirmed a defect in the immune response to the virus – an overactive protein on immune system cells called PD-1. This discovery, the researchers argue, will likely pave the way for the development of new therapeutic strategies.

PD-1 – also known as the programmed death-1 receptor – was discovered in 1992 by Tasuku Honjo, PhD, of Kyoto University in Japan. Dr. Honjo's initial work demonstrated that PD-1 plays a role in calming down the immune system when dealing with a chronic infection, in order to prevent the immune system from becoming overly stimulated and ultimately attacking healthy cells and tissues in the body.

While experts agree that a hyperactive immune system can be harmful to people with HIV, some have suggested that the biological processes responsible for calming T cells may actually prevent the immune system from doing what it needs to do in terms of fighting the virus.

The new research, conducted by three teams of scientists in Boston, Montreal, and Bethesda, suggests that PD-1 may have too much of a calming effect on the immune system and that targeting it may help give T cells the spark they need to be more aggressive against HIV.

In the first report, published in Nature, Bruce Walker, MD, of Harvard Medical School in Boston and his colleagues collected blood samples from 71 HIV-positive people who had not yet started HIV treatment. His group compared these samples to those taken from patients currently on therapy.

The primary goal of Dr. Walker's group's research was to look at PD-1 "expression" on what are known as HIV-specific CD8 cells (T8 cells) – specific types of T cells that have been programmed to hunt down and destroy other immune system cells infected with HIV. The study found that untreated HIV infection is associated with high levels of activated PD-1 on these CD8 cells. In fact, the higher the amount of PD-1 on these cells, the less active these cells were. In the samples taken from the HIV-positive people on treatment, activated PD-1 was decreased, which was associated with increased CD8 cell function.

The second report, published by Rafick-Pierre Sékaly, MD, of the Université de Montréal and his colleagues, was published in Nature Medicine.

By way of background information, Dr. Sékaly's group explained in their paper that blocking the activity of PD-1 in virus-infected mice allows "exhausted" CD8 cells to proliferate, go about their infection-fighting activity, and reduce viral load.

The Canadian team's research confirmed Dr. Walker's group's observation, that PD-1 was prevalent on HIV-specific CD8 cells. This correlated with higher viral loads and reduced cell activity. Dr. Sékaly's team also looked at CD8 cells responsible for targeting cells infected with cytomegalovirus (CMV), an infection that is almost always kept in check in people with moderate-to-healthy immune systems. There was no increased PD-1 activity on these cells, providing additional evidence of a relationship between this protein and lagging immune system activity.

Additionally, Dr. Sékaly's group demonstrated that blocking PD-1 enhanced the ability of HIV-specific CD8 cells to survive, proliferate, and produce the molecules it needs to kill HIV-infected cells in the body. "The most important discovery made in this study arises from the fact that by targeting this protein, we succeeded in preventing the virus from making immune system cells dysfunctional," Dr. Sékaly said.

The third study, to be published by Richard Koup, MD, of the National Institutes of Health's Vaccine Research Center in Bethesda and his colleagues in an upcoming issue of the Journal of Experimental Medicine, suggests that the activity of PD-1 actually causes HIV-specific CD8 cells to die.

"It's a rare occurrence for three teams to work together on attacking a major problem," noted Dr. Sékaly. "Up until now, the virus has been more or less invincible. By combining our efforts, we found the missing link that may enable us to defeat the virus." He added that discussions with partners are underway to apply these research findings to the development of therapies targeting PD-1, such as synthetic antibodies against the protein.

Clinical trials, Dr. Sékaly reckons, could start sometime in the coming year.