- BOSTON - New,
three-dimensional
images from researchers at Dana-Farber Cancer Institute provide the fullest
picture yet of how the AIDS virus blunts the immune system's ability to
mount an attack against infections and cancer.
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- The images, contained in a study in the Sept. 11 issue
of the Proceedings of the National Academy of Sciences, provide a detailed,
close-up look at one part of the meeting between infected cells and
"helper"
T cells, which mobilize the body's defenses against disease. A comparison
of those images with images of the meeting between helper T cells and HIV-1
(the virus that causes AIDS) shows how HIV-1 mimics other enemy invaders
and essentially blindfolds the T cells to the presence of infection and
cancer.
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- "This work enables us to piece together an exact
picture of a key part of the process by which the immune system is alerted
to disease, and to understand how HIV subverts that process," says
the study's lead author, Jia-huai Wang, Ph.D., of Dana-Farber. "It
provides a pictorial explanation for immunodeficiency - the process by
which HIV undermines the immune system's ability to resist invaders. And
it will help in the development of AIDS therapies that target the
vulnerable
points of HIV infection."
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- The study is the latest chapter in a scientific saga
that began 20 years ago, when Dana-Farber researchers discovered a molecule
called CD4 on the surface of helper T cells. CD4 serves as an antenna,
enabling helper T cells to probe other cells for signs of infection and,
in the case of HIV, a keyhole by which the virus gains entry to the cell
and subverts its function.
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- When a helper T cell encounters another cell, it uses
various probes on its surface - known as receptors and CD4 coreceptors
- to examine protein fragments arrayed on the cell's surface. The
fragments
tell the T cell whether the target cell is normal, and to be left unharmed,
or infected, and to be destroyed. The protein fragments are cupped inside
tiny "holders" called class II major histocompatibility complexes
(class II MHCs).
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- Two years ago, Wang and senior author Ellis Reinherz,
MD, of Dana-Farber, used X-ray crystallography to produce the first
three-dimensional
images of a portion of the T cell receptor bound to protein fragments in
a class II MHC. The new study provides the last piece of the puzzle:
combined
with crystallography images obtained by other researchers, scientists now
have a complete structural rendering of a T cell receptor, CD4 coreceptor,
and protein fragment enmeshed with a class II MHC.
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- The coupling, it turns out, is a rather tenuous one.
Only a small corner of the CD4 molecule directly contacts the MHC. The
structures appear to form a V: the T cell receptor and CD4 coreceptor
spread
apart from the areas of contact with the class II MHC.
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- The significance of this finding became apparent when
researchers compared the new image with an image of CD4 bound to a protein
on the surface of HIV-1.
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- HIV uses CD4 as an anteroom for infecting T cells. A
protein on the surface of HIV, called gp120, latches onto the CD4
coreceptor,
beginning a process by which HIV is ushered inside the cell.
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- When the Dana-Farber researchers compared the union
between
CD4-MHC with the one between CD4-gp120, they found that gp120 covers a
greater portion of CD4. The result is helper T cells form a stronger bond
with HIV than they do with cells that help protect against infections.
HIV, in effect, blindfolds helper T cells to the presence of enemy
invaders,
hampering the body's ability to fight not only HIV itself, but other
infections
as well.
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- "We now have a graphic representation of how HIV
hinders the immune response," Reinherz says. "We've known in
the past that the grip between HIV and helper T cells is stronger than
the one between T cells and other normal components of the body's immune
system. Now we know why."
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- The finding offers important information in the quest
for new AIDS treatments. Therapies that interfere with HIV's ability to
link with helper T cells by binding to gp120, for example, might offer
a promising way of preventing HIV infection while maintaining the body's
natural ability to counter disease.
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- ___
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- The work is a joint effort between Dana-Farber Cancer
Institute scientists and colleagues at Argonne National Laboratory, and
was supported by the National Institute of Allergy and Infectious Diseases
and the U.S. Department of Energy.
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- Dana-Farber Cancer Institute www.danafarber.org
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC),
a designated comprehensive cancer center by the National Cancer
Institute.
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