February 14th, 2007
In a finding that
could have profound implications for AIDS vaccine design, researchers
led by a team at the National Institute of Allergy and Infectious
Diseases (NIAID), part of the National Institutes of Health (NIH),
have generated an atomic-level picture of a key portion of an HIV
surface protein as it looks when bound to an infection-fighting
antibody. Unlike much of the constantly mutating virus, this protein
component is stable and more importantly, say the researchers
appears vulnerable to attack from this specific antibody,
known as b12, that can broadly neutralize HIV.
“Creating an HIV vaccine is one of the great scientific challenges
of our time,” says NIH Director Elias A. Zerhouni, M.D. “NIH
researchers and their colleagues have revealed a gap in HIV’s
armor and have thereby opened a new avenue to meeting that challenge.”
The research team was led by Peter Kwong, Ph.D., of NIAID’s
Vaccine Research Center (VRC). His collaborators included other
scientists from NIAID and the National Cancer Institute, NIH, as
well as investigators from the Dana-Farber Cancer Institute, Boston,
and The Scripps Research Institute in La Jolla, CA. Their paper
appears in the February 15 issue of Nature and is now available
“This elegant work by Dr. Kwong and his colleagues provides
us with a long-sought picture of the precise interaction between
the HIV gp120 surface protein and this neutralizing antibody,”
says NIAID Director Anthony S. Fauci, M.D. “This finding could
help in the development of an HIV vaccine capable of eliciting a
robust antibody response.”
For years, AIDS vaccine developers have been stymied by the seemingly
unlimited ways HIV eludes natural and vaccine-induced immune defenses.
Notes Dr. Kwong, “The more we learned about HIV, the more
we realized just how many levels of defense the virus has against
attacks by the immune system.” For example, not only does
HIV mutate rapidly and continuously defeating attempts by
the immune system to identify and destroy it the virus is
also swathed by sugary molecules. This nearly impenetrable sugar
cloak prevents antibodies from slipping in and blocking the proteins
the virus uses to latch onto a cell and infect it.
In 1998, Dr. Kwong and colleagues published the first X-ray snapshot
of the core of HIV gp120 as it attaches to a cellular receptor known
as CD4. That image gave researchers a glimpse of some sites on the
virus that could be targets of drugs or vaccines, but it also revealed
the extent of HIV’s overlapping defenses. For example, scientists
subsequently learned that CD4-gp120 contact causes gp120 to change
shape, a viral feint known as conformational masking, which acts
to further shield HIV from immune system attack.
While the earlier study provided a picture of the CD4-gp120 complex,
the new finding delineates the precise stepwise engagement between
gp120 and CD4. The researchers found that the gp120-CD4 encounter
starts with a highly focused contact and then expands to a broader
surface that stabilizes the interaction.
“The first contact is like a cautious handshake, which then
becomes a hearty bear hug,” says Gary Nabel, M.D., Ph.D.,
director of NIAID’s VRC and co-author of the new paper.
An effective HIV vaccine likely needs to induce antibodies that
can sense and destroy multiple HIV strains. Scientists have sought
such broadly neutralizing antibodies by studying the blood of people
whose immune systems appear to hold the virus at bay for long periods
of time b12 is one of these rare, broadly neutralizing antibodies.
Until now, no one had succeeded in determining the detailed structure
of b12 in complex with gp120. It was extremely difficult to crystallize
b12 bound to gp120, says Dr. Kwong, in part due to the inherently
flexible nature of the chemical bonds in gp120. To overcome the
problem, the investigators created a variety of gp120s and eventually
made the protein stiff enough to capture a picture of it in complex
with b12. They saw that b12 binds gp120 at the same point where
gp120 initially attaches to CD4. Unlike the gp120-CD4 interactions,
however, b12 can latch onto the site of CD4’s first contact
without requiring a shape change in gp120 to create a stable bond
between the two molecules. Essentially, the scientists found that
the initial point of CD4 contact is a site of gp120 weakness because
it is the site of recognition called an epitope for
“One of our primary goals is to develop HIV vaccines that
can stimulate broadly neutralizing antibodies,” says Dr. Nabel.
“The structure of this gp120 epitope, and its susceptibility
to attack by a broadly neutralizing antibody, shows us a critical
area of vulnerability on the virus that we may be able to target
with vaccines. This is certainly one of the best leads to come along
in recent years.”
For an image of the b12 antibody in contact with a critical target
on HIV-1 gp120, see http://www3.niaid.nih.gov/news/newsreleases/2007/b12antibodyimage.htm.
News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at <http://www.niaid.nih.gov>.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs,
References: T Zhou et al. Structural definition
of a conserved neutralization epitope on HIV-1 gp120. Nature
DOI: 10.1038/Nature05580 (2007).
PD Kwong et al. Structure of an HIV gp120 envelope glycoprotein
in complex with CD4 receptor and a neutralizing human antibody.
Nature 393:648-59 (1998).
Vaccine Research Center Structural Biology Laboratory <http://www.niaid.nih.gov/vrc/labs_kwong.htm>.