From Scripps: “TSRI Scientists Discover Antibodies that Target Holes in HIV’s Defenses”

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Scripps Research Institute

September 12, 2016

New Findings Could Lead to New AIDS Vaccine Candidates

A new study from scientists at The Scripps Research Institute (TSRI) shows that “holes” in HIV’s defensive sugar shield could be important in designing an HIV vaccine.

It appears that antibodies can target these holes, which are scattered in HIV’s protective sugar or “glycan” shield, and the question is now whether these holes can be exploited to induce protective antibodies.

“It’s important now to evaluate future vaccine candidates to more rapidly understand the immune response they induce to particular glycan holes and learn from it,” said TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.

The study, published recently in the journal Cell Reports, was co-led by Burton, TSRI Associate Professor Andrew Ward, also of CHAVI-ID, and Rogier W. Sanders of the University of Amsterdam and Cornell University.

A Clue to Stopping HIV

Every virus has a signature structure, like the architecture of a building. By solving these structures, scientists can put together a blueprint showing where HIV is vulnerable to infection-blocking antibodies.

In the 1990s, scientists discovered that HIV can have random holes in its protective outer shell of glycan molecules. Until now, however, scientists weren’t sure if antibodies could recognize and target these holes.

Researchers at Cornell and TSRI had previously designed a stabilized version of an important HIV protein, called the envelope glycoprotein (Env) trimer, to prompt rabbit models to produce antibodies against the virus. In the new study, the plan was to reveal HIV’s vulnerabilities by examining where the antibodies bound the virus.

“From work on HIV-positive individuals, we knew that the best way to understand an antibody response is to isolate the individual antibodies and study them in detail,” said Laura McCoy, a TSRI, IAVI and CHAVI-ID researcher now at University College London, who served as co-first author of the study with TSRI Senior Research Associate Gabriel Ozorowski, also of TSRI and CHAVI-ID, and Marit J. van Gils of the University of Amsterdam.

To their surprise, when the researchers examined the rabbits’ antibodies, they found three rabbits had produced antibodies that targeted the same hole in Env. It appeared that antibodies could indeed target holes in the glycan shield.

“This opened up a whole new concept,” said Ozorowski.

If the immune system was targeting this hole—preferring it to other vulnerable spots on Env—maybe holes would be especially important in designing vaccine candidates.

Toward Better Antibodies

By analyzing the genetic sequences of thousands of strains of HIV, the researchers found that 89 percent of strains appear to have a targetable hole in the Env. The virus has a defense mechanism though—it quickly mutates to fill in these gaps.

The researchers speculate that future vaccines might prompt the immune system to create antibodies to target holes. “Targeting a hole could help the immune system get its foot in the door,” Ozorowski said. Alternatively, the holes may prove a distraction and should be filled in so the immune system can focus on targeting better sites for neutralizing the virus.

Burton said researchers must investigate the different possibilities, but he emphasized that this new understanding of glycan holes could help researchers narrow down the field of molecules needed in potential HIV vaccines.

Ward added that this same method of “rational” vaccine design—where researchers use a virus’s precise molecular details to prompt the immune system to produce specific antibodies—can also be applied to efforts to fight other viruses, such as influenza and Ebola viruses.

In addition to Burton, Ward, Sanders, McCoy, Ozorowski and van Gils, authors of the study, “Holes in the glycan shield of the native HIV envelope are a target of trimer-elicited neutralizing antibodies,” were Terrence Messmer, Bryan Briney, James E. Voss, Daniel W. Kulp, Devin Sok, Matthias Pauthner, Sergey Menis and Jessica Hsueh of TSRI, IAVI and CHAVI-ID; Christopher A. Cottrell, Jonathan L. Torres and Ian A. Wilson of TSRI and CHAVI-ID; Matthew S. Macauley of TSRI; and William R. Schief of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

This study was supported by CHAVI-ID (grant UM1AI100663), the National Institutes of Health’s HIV Vaccine Research and Design (HIVRAD) Program (grant P01 AI110657), the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD, grants OPP1084519 and OPP1115782), a Marie-Curie Fellowship (FP7-PEOPLE-2013-IOF), the Aids Fonds Netherlands (grant 2012041), EMBO (grant ASTF260-2013), the Netherlands Organization for Scientific Research (grant 917.11.314) and the European Research Council (grant ERC-StG- 2011-280829-SHEV).

See the full article here .

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The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG) From Scripps Research Institute.

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The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.