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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