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HIV Surface Proteins Finally Caught Going Au Naturel

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Science  01 Nov 2013:
Vol. 342, Issue 6158, pp. 546-547
DOI: 10.1126/science.342.6158.546-b
Mimicking nature.

"Near-native" HIV trimers have a consistent shape (antibodies attached in gray), but non-native trimers always differ.

CREDIT: ANDREW WARD/SCRIPPS RESEARCH INSTITUTION

After nearly 2 decades of effort, researchers have artificially produced and structurally analyzed proteins that they say closely mimic those naturally appearing on the surface of HIV. Many investigators have high hopes that these "near native" versions of the proteins will usher in a new era of AIDS vaccine design, just as new insights into protein structure have invigorated the quest to develop a vaccine for respiratory syncytial virus (RSV) (see main story). In the shorter term, the three new studies—two published online this week in Science—will stoke long-standing debates about the precise shape of these proteins, which cluster into what resemble mushrooms sprouting from the viral surface, and how they stimulate an immune response to HIV.

HIV infects cells via two attached surface proteins that bud through the viral membrane in groups of three, called trimers (the mushrooms). For technical reasons, membrane-bound trimers are difficult to produce in large enough quantities for fine-grained structural analysis. When researchers manufacture these proteins without the membrane anchoring them, the fragile trimers fall apart, making them impossible to study. Many groups have chosen to make specific amino acid changes so the trimers hold together, but these are far from the native form.

The two Science papers describe how a structural biology team led by Ian Wilson of the Scripps Research Institute in San Diego, California, finally got high-resolution portraits of the near-native trimers. Key to their success were stable, lab-made versions of the proteins, designed by immunologist John Moore of the Weill Medical College of Cornell University in New York City and his co-workers. "This has been on the Top 10 Most Wanted list for structural biologists," says Peter Kwong, who does structural analyses of both HIV and RSV at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

The new findings promise to guide attempts to devise immunogens—vaccine components—that can trigger production of so-called broadly neutralizing antibodies (bNAbs), which many immunologists believe a successful HIV vaccine needs to elicit. (Isolated from infected people, bNAbs offer them little help because they take years to appear and are made in tiny amounts.) Unlike ordinary antibodies, which the virus easily evades by mutating or which don't have neutralizing power to begin with, bNAbs can thwart many variants of the virus (Science, 13 September, p. 1168). "It's elegant, beautiful work," says VRC Director John Mascola. "I think we'll see a whole new wave of immunogen design that will come out of this."

Moore and colleagues spent 15 years attempting to create stable versions of the native trimer outside of a membrane, adding chemical bonds and removing parts of the proteins to enable them to maintain their native configuration. The result could help settle contentious debates about the trimer's structure (Science, 2 August, p. 443). Kwong and others say the new structures are especially convincing because two different techniques—x-ray crystallography and cryo-electron microscopy—independently arrived at the same images. A group at the U.S. National Cancer Institute that analyzed earlier versions of the trimers used in the Science studies confirms the new structures in a 23 October online report in Nature Structural & Molecular Biology.

Wilson says the sharper picture of the near-native trimers may give vaccine designers new ideas about the infection process and how to thwart it. Moore suggests that because native trimers trigger bNAbs naturally, they might work better as immunogens than the non-native trimers other researchers have been studying. Test-tube studies also show that bNAbs bind better to native trimers. "I'm not saying every bNAb ever induced must have been derived from a native trimer, but I think it's reasonable that many of them will have been," Moore says.

Moore's lab-made trimers have not been tested in animals, although those studies are under way. Several groups making immunogens with non-native structures caution that just because a bNAb binds to a trimer, it doesn't mean that trimer can teach an immune system to make the same antibody. "These two papers provide some exquisite structural biology that is very appealing, however beauty is in the eye of the beholder, and, in this respect, it's the immune system that is the final arbiter," says Robin Shattock, an immunologist at Imperial College London. "So in the race to induce broadly neutralizing antibodies, only time will tell whether these structures are a game changer or an incremental step."

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