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.
