Scientists Capture Most Detailed Picture Yet of Key AIDS Protein
The finding represents a scientific feat as well as progress toward an HIV vaccine
LA JOLLA, CA-October 31, 2013 - Collaborating scientists at The Scripps Research Institute (TSRI) and Weill Cornell
Medical College have determined the first atomic-level structure of the tripartite HIV envelope protein-long considered one of the
most difficult targets in structural biology and of great value for medical science.
The new findings provide the most detailed picture yet of the AIDS-causing virus's complex envelope, including sites that future vaccines
will try to mimic to elicit a protective immune response.
"Most of the prior structural studies of this envelope complex focused on individual subunits; but we've needed the structure of the full
complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine," said Ian A. Wilson, the Hansen
Professor of Structural Biology at TSRI, and a senior author of the new research with biologists Andrew Ward and Bridget Carragher of
TSRI and John Moore of Weill Cornell.
The findings are published in two papers in Science Express , the early online edition of the journal Science, on October
31, 2013.
A Difficult Target
HIV, the human immunodeficiency virus, currently infects about 34 million people globally, 10 percent of whom are children, according
to World Health Organization estimates. Although antiviral drugs are now used to manage many HIV infections, especially in developed
countries, scientists have long sought a vaccine that can prevent new infections and perhaps ultimately eradicate the virus from
the human population.
However, none of the HIV vaccines tested so far has come close to providing adequate protection. This failure is due largely to the
challenges posed by HIV's envelope protein, known to virologists as Env.
Env's structure is so complex and delicate that scientists have had great difficulty obtaining the protein in a form that is suitable
for the atomic-resolution imaging necessary to understand it.
"It tends to fall apart, for example, even when it's on the surface of the virus, so to study it we have to engineer it to be more
stable," said Ward, who is an assistant professor in TSRI's Department of Integrative Structural and Computational Biology.
Illuminating Infection
In the current work the Weill Cornell-TSRI team was able to engineer a version of the Env trimer (three-component structure) that has
the stability and other properties needed for atomic-resolution imaging, yet retains virtually all the structures found on native Env.
Using cutting-edge imaging methods, electron microscopy (spearheaded by graduate student Dmitry Lyumkis) and X-ray crystallography
(led by Jean-Philippe Julien, a senior research associate in the Wilson lab), the team was then able to look at the new Env trimer.
The X-ray crystallography study was the first ever of an Env trimer, and both methods resolved the trimer structure to a finer
level of detail than has been reported before.
The data illuminated the complex process by which the Env trimer assembles and later undergoes radical shape changes during infection and
clarified how it compares to envelope proteins on other dangerous viruses, such as flu and Ebola.
"It has been a privilege for us to work with the Scripps team on this project," said Moore on behalf of the Weill Cornell group. "Now we
all need to harness this new knowledge to design and test next-generation trimers and see if we can induce the broadly active neutralizing
antibodies an effective vaccine is going to need."
Other contributors to the studies, "Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer," and "Crystal
structure of a soluble cleaved HIV-1 envelope trimer ," included TSRI's Natalia de Val, Devin Sok, Robyn L. Stanfield and Marc C. Deller;
and Weill Medical College's Rogier W. Sanders (also at Academic Medical Center, Amsterdam), Albert Cupo and Per-Johan Klasse. In
addition to Wilson, Ward and Carragher, senior participants at TSRI included Clinton S. Potter and Dennis Burton.
The research was supported in part by the National Institutes of Health (HIVRAD P01 AI82362, CHAVI-ID UM1 AI100663, R01 AI36082, R01
AI084817, R37 AI36082, R01 AI33292), the US NIH NIGMS Biomedical Research Technology Program (GM103310) and the International AIDS
Vaccine Initiative Neutralizing Antibody Consortium and Center.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research
in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in
laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that
evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now
employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists-including
three Nobel laureates-work toward their next discoveries. The institute's graduate program, which awards PhD
degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information,
see www.scripps.edu .
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Source: The Scripps Research Institute
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