CHICAGO Dec 19 U.S. scientists have discovered
the basic mechanisms that allow HIV to wipe out the body's
immune system and cause AIDS, which could lead to new approaches
to treatment and research for a cure for the disease that
affects 35 million people around the world.
Instead of actively killing immune system cells known as CD4
T cells, much of the damage done by HIV occurs when the virus
tries to invade these cells and fails, triggering an innate
immune response that causes the cells to self-destruct in a
fiery kind of cell suicide known as pyroptosis.
The findings, published simultaneously in the scientific
journals Science and Nature, also suggest that an experimental
anti-inflammatory drug owned by Vertex Pharmaceuticals Inc
that has already been tested in people with epilepsy
could be repurposed as a possible new treatment for AIDS.
"Our papers deal with the fundamental issue that causes
AIDS, and that is the loss of CD4 T cells," said Dr Warner
Greene of the Gladstone Institutes, an independent biomedical
research nonprofit based in San Francisco, whose lab produced
the research in both papers.
Dr Anthony Fauci, director of the National Institute of
Allergy and Infectious Disease, said the papers offer an
"elegant" solution to a question that has eluded scientists
since the virus was first identified in 1983.
Greene said for years, scientists had thought that HIV
killed immune system cells by infecting them directly, hijacking
their DNA machinery and turning them into virus-producing
But this only happens to a small portion of CD4 T cells. In
a series of experiments in human spleen, tonsil and lymph node
tissues from HIV-infected patients, the Gladstone scientists
discovered that the real damage of HIV infection occurs in
so-called "bystander cells," the most common type of CD4 T cell.
These cells are in a resting state, so when the virus
attacks, it is unable to hijack them, and aborts the attempt.
But the damage is done. These so-called abortively infected
immune cells release a protein that activates an enzyme called
caspase-1, which causes the highly inflammatory form of cell
"The cell is committing suicide in a vain attempt to protect
the host," Greene said. "The abortive process releases a call
for help from new CD4 cells, who then fall victim to this fiery
In the paper published in Science, the Gladstone team
identified a mechanism that detects the damaged cells and
triggers this cell death pathway.
"This idea that CD4 depletion is more of a cellular suicide
than it is a murder by the virus is a new and important
concept," Greene said.
In the paper published in Nature, the team explored the
implications of blocking this cellular suicide with experiments
using anti-inflammatory drugs that block the caspase-1 enzyme,
including the Vertex drug VX-765.
Greene said the company tested the treatment in patients
with a chronic seizure disorder who would not respond to normal
anti-epileptics, but the effect was not strong enough to
What they did find in a six-week clinical trial in people is
that the drug was safe and well-tolerated.
"We would like to see if that drug could be repurposed to
prevent inflammation in CD4 T cell loss in HIV infection,"
Gladstone is in talks with Vertex to gain access to the drug
for clinical trials as a potential new treatment for HIV
infection. Such a drug could have three potential applications.
It could be used globally as a stop-gap treatment for the
16 million individuals who are infected with HIV but do not have
access to antiretroviral therapy or ART, the highly effective
medicines that keep HIV from replicating in the body.
Because the drug fights the inflammatory response linked
with HIV infection, it might also be useful in addition to ART
as a way of preventing the long-term consequences of HIV
infection, such as early dementia, heart attacks and cancer.
Greene thinks the drug might even be useful in the research
for an HIV cure, helping to flush out parts of the virus that go
into hiding and cause the infection to start up again once
people stop taking antiretroviral therapy.
At this point, all of these potential uses are theoretical,
Fauci said. "It still remains to be seen what the ultimate
practical usage of this is, but nonetheless, it's still a
Greene said his team is in negotiations with Vertex for
access to its drug, and hopes to come to an agreement soon as to
how to proceed. "For the benefit of HIV-infected individuals,
this merits testing."