Towards an AIDS Vaccine:
TSRI Scientists Describe Unusual Antibody That Targets HIV
By Jason Socrates
Bardi
A group of scientists from The Scripps Research Institute
(TSRI) and several other institutions has solved the structure
of an antibody that effectively neutralizes human immunodeficiency
virus (HIV), the virus that causes acquired immunodeficiency
syndrome (AIDS).
The antibody binds to sugars on the surface of HIV and effectively
neutralizes the virus because of its unique structure, which
is described in the latest issue of the journal Science.
"What we found was an unusual configuration of the antibody
in which its two Fab domains—the antigen recognition
units—are 'interdigitating' with each other," says TSRI
Professor Ian Wilson, one of two TSRI professors who led the
research. "Nothing like this has ever been seen before."
This new structure is an important step toward the goal
of designing an effective vaccine against HIV, and it gives
the researchers a new way to design antibodies in general.
"It may enable us to make antibodies that recognize whole
new sets of molecules," says TSRI Professor Dennis Burton,
the other TSRI investigator who led the research.
The Problem of HIV and Antibodies
HIV causes AIDS by binding to, entering, and ultimately
killing T helper cells, which are immune cells that are necessary
to fight off infections by common bacteria and other pathogens.
As HIV depletes the body of T helper cells, common pathogens
can become potentially lethal.
The latest statistics are grim. The World Health Organization
estimates that around 40 million people are living with HIV
worldwide. During 2001 alone, more than four million men,
women, and children succumbed to the disease, and by the end
of that year, the disease had made orphans of 14 million children.
In the United States, 40,000 people are infected with HIV
each year. One of the most compelling medical challenges today
is to develop a vaccine that will provide complete prophylactic
protection to someone who is later exposed to this virus.
An important part of such a vaccine will be a component that
elicits or induces effective neutralizing antibodies against
HIV in the blood of the vaccinated person.
Also called immunoglobins, antibodies are the basis for
many existing vaccines, including those against measles, polio,
hepatitis B, and hepatitis A. HIV antibodies are produced
by the body's B cells after HIV enters the bloodstream. During
such an immune response, the antibodies circulate through
the blood. Good antibodies bind to and "neutralize" the virus,
making it unable to invade cells. Because neutralizing antibodies
attack the virus before it enters cells, they could conceivably
be used to prevent HIV infection if they were present prior
to virus exposure. A vaccine would seek to elicit these neutralizing
antibodies.
This is easier said than done. The body makes lots of antibodies
against HIV, but they are almost always unable to neutralize
the virus. Much of the viral surface is coated with carbohydrates
(sugars), which are hard for the immune system to attack because
these sugars are made by human cells and attached by human
proteins. In other words, they are "self" and should not be
recognized by antibodies.
Interlocking Arms
However, in rare instances some people have produced antibodies
that broadly neutralize HIV. One such antibody, called 2G12,
was isolated from such an HIV-positive individual about a
decade ago by Hermann Katinger, a doctor at the Institute
for Applied Microbiology of the University of Agriculture
in Vienna, Austria and one of the authors on the paper. This
antibody is not like ordinary antibodies.
"The Fab [antigen recognition] arms are interlocked," says
Burton. "That is a unique arrangement, and it is good for
recognizing a cluster of shapes like sugars on a virus."
The 2G12 antibody forms an unusual "dimer" interface where
two antibodies create an unusual multivalent binding interface
with multiple binding sites that recognizes an unusual arrangement
of 2-3 "oligomannose" sugars on the surface of protein spikes
called gp120 that decorate the coat of HIV. This allows the
antibody to properly target HIV virions as foreign pathogens.
The sugars are human but their arrangement is foreign—and
it is this arrangement that the antibodies recognize.
These results are a step in the direction of designing an
effective AIDS vaccine because it reveals what these neutralizing
antibodies can look like. The next step is to use the structure
of the antibody as a template to design an "antigen" that
would stimulate the human immune system to make 2G12 or similar
broadly neutralizing antibodies against HIV.
The results are also important because the structure of
the antibody is something that has never been seen before.
"Can we now," asks Wilson, "use this [knowledge] to engineer
antibodies with higher affinity against other antigens or
clusters of antigens?"
The TSRI study combined experts from several institutions
in addition to those at TSRI, including Pauline M. Rudd, and
Raymond A. Dwek from the Glycobiology Institute at Oxford
University in the United Kingdom. Also involved were researchers
in the Department of Biological Science and Structural Biology
at Florida State University in Tallahassee.
The research article, "Antibody Domain Exchange is an Immunological
Solution to Carbohydrate Cluster Recognition" is authored
by Daniel A. Calarese, Christopher N. Scanlan, Michael B.
Zwick, Songpon Deechongkit, Yusuke Mimura, Renate Kunert,
Ping Zhu, Mark R.Wormald, Robyn L. Stanfield, Kenneth H. Roux,
Jeffery W. Kelly, Pauline M. Rudd, Raymond A. Dwek, Hermann
Katinger, Dennis R. Burton, and Ian A. Wilson and appears
in the June 27, 2003 issue of the journal Science.
The research was supported by The Skaggs Institute for Research,
which funds The Skaggs Institute for Chemical Biology at TSRI.
Grants from the National Institute of Allergy and Infectious
Diseases (NIAID), the National Institute of General Medical
Sciences (NIGMS), and the International AIDS Vaccine Initiative
(IAVI) also supported the research.
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Novel Architecture
of Antibody 2G12
A) Overall structure
of a "typical" Fab monomer, with the light and heavy chains
in grey and purple, respectively. B) Structure of the 2G12
Fab monomer. The heavy chain clearly separates from its usual
interaction with the light chain. The monomer does not exist
in the crystal, but only in the context of the domain-swapped
dimer. C) Structure of the two domain-swapped Fab molecules,
as they assemble in the crystal. The light chains are shown
in grey, with the heavy chains shown in blue and purple.
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