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Is High-Tech View of HIV Too Good to Be True?

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Science  02 Aug 2013:
Vol. 341, Issue 6145, pp. 443-444
DOI: 10.1126/science.341.6145.443
Unresolved debate.

Is this 6-Å resolution structure of HIV's surface proteins jutting through a cell membrane real?

CREDIT: Y. MAO ET AL., PNAS 110 (23 JULY)

Structural biologists over the past 15 years have used increasingly sophisticated tools to offer fantastically detailed views of HIV's surface proteins. On 11 June online, the Proceedings of the National Academy of Sciences (PNAS) published the most exquisite yet, showing the molecular architecture of the proteins in the finest resolution ever. It comes from a prominent research group and promises to guide HIV vaccine design for years. If it is right.

Several respected HIV/AIDS researchers are wowed by the work. But others—structural biologists in particular—assert that the paper is too good to be true and is more likely fantasy than fantastic. "That paper is complete rubbish," charges Richard Henderson, an electron microscopy pioneer at the MRC Laboratory of Molecular Biology in Cambridge, U.K. "It has no redeeming features whatsoever."

Imaginary image.

Improperly used technique from cryo-EM can recover Einstein from white noise (right).

CREDIT: M. SHATSKY ET AL., JOURNAL OF STRUCTURAL BIOLOGY 166 (2009)

That scorching assessment is especially startling given that the work comes from the lab of Joseph Sodroski, a virologist at the Dana-Farber Cancer Institute in Boston. He has published nearly 400 papers, including more than three dozen in Science, Nature, and Cell. Sodroski is low-key and anything but a lightning rod for criticism. Yet during the past year, Science has learned, these three top-tier journals and at least one other rejected various iterations of his lab's findings using a technique called cryo-electron microscopy (cryo-EM), which visualizes individual proteins after rapid freezing at liquid nitrogen temperatures. Henderson, who says that he wrote critical reviews of the work for two publications, is leading a pack of structural biologists who are in an uproar that PNAS published it.

Sodroski and first author Youdong Mao, a postdoc in Sodroski's lab, are not yielding any ground. "We stand behind our published work," they write in an e-mail to Science. "If anyone has specific scientific issues with our methods, results or interpretations, they should voice their concerns in the proper scientific forums. We will respond to such concerns in the peer-reviewed scientific literature."

The PNAS paper shows a 6-ångström view of HIV's surface proteins gp120 and gp41, which are attached to each other and appear in clusters of three called trimers. In contrast to old-fashioned electron microscopic methods, cryo-EM allows visualization of the trimers without addition of stains that can distort shapes. If the results hold, Sodroski, Mao, and co-workers have unveiled the sharpest view of the trimers ever captured in the precise configuration that the immune system sees them. This could lead to new insights about how antibodies capable of stopping HIV bind to the virus.

Most of the structural biologists and HIV/AIDS researchers Science spoke with, including several reviewers, did not want to speak on the record because of their close relations with Sodroski or fear that they'd be seen as competitors griping—and some indeed are competitors. Two main criticisms emerged. Structural biologists are convinced that Sodroski's group, for technical reasons, could not have obtained a 6-Å resolution structure with the type of microscope they used. The second concern is even more disturbing: They solved the structure of a phantom molecule, not the trimer. "Preparation of cryo-EM specimens that are capable of producing high-resolution structures of membrane proteins in solution is challenging," says structural biologist Sriram Subramaniam, a cryo-EM specialist at the U.S. National Cancer Institute in Bethesda, Maryland, who has published 9-Å views of HIV trimers. Like Henderson and other structural biologists interviewed, Subramaniam doubts that Sodroski's group had any HIV particles in their samples.

The essential problem, they contend, is that Sodroski and Mao "aligned" their trimers to lower-resolution images published before, aiming to refine what was known. This is a popular cryo-EM technique but requires convincing evidence that the particles are there in the first place and rigorous tests to ensure that any improvements are real and not the result of simply finding a spurious agreement with random noise. "They should have done lots of controls that they didn't do," Subramaniam asserts. In an oft-cited experiment that aligns 1000 computer-generated images of white noise to a picture of Albert Einstein sticking out his tongue, the resulting image still clearly shows the famous physicist. "You get a beautiful picture of Albert Einstein out of nothing," Henderson says. "That's exactly what Sodroski and Mao have done. They've taken a previously published structure and put atoms in and gone down into a hole." Sodroski and Mao declined to address specific criticisms about their studies.

Beatrice Hahn, a virologist at the University of Pennsylvania and a member of the National Academy of Sciences, served as editor of the PNAS paper, meaning that she selected the referees and oversaw the review process. "This is about the hottest-button issue I've encountered in my 30-year career," says Hahn, who is well-known for her studies of HIV's origins. "For the past almost 2 years now, I've watched some of the criticisms and the responses and both sides are certainly reasonable." Hahn decided that it was time to intervene. "When there's a potential leap that's either totally wrong or right, that information has to be made public [in a journal]. All sorts of people can look at it and make up their minds."

Hahn acknowledged that she is not versed in the complicated cryo-EM technique enough "to really judge one way or the other" whether the criticisms are legitimate. She says Sodroski told her that Mao previously used cryo-EM to study graphite and routinely pieced together sub optimal images, which may help explain how he achieved a higher resolution than specialists who study only biological samples. She insists that the paper received a bona fide peer review at PNAS and urges people to remember that Sodroski has a record of producing credible work. "My gut tells me that Joe is right."

Bette Korber, an immunologist at the Los Alamos National Laboratory in New Mexico who uses models of HIV trimers to help design vaccines, admires how Sodroski is handling the criticism. "He is systematically addressing the points raised in reviews or in conversation with other scientists in the field," Korber says. "I've known Joe for most of my professional career, and find him to be a person of great integrity, and I am optimistic he will continue to be able address the concerns of others as research advances in this area."

Sodroski impressed many HIV/AIDS researchers in March 2012, when he first presented the work at the Conference on Retroviruses and Opportunistic Infections, a meeting Hahn helps organize. By then, the work had already sparked skepticism in cryo-EM circles. When he first shopped a paper claiming a 2.6-Å structure—near atomic level—Henderson, for one, was incredulous. "If true, several synchrotrons in the world and cryo-EM specialists would all be out of business," he says, noting that he refereed conflicting reviews of this version of the paper for Nature.

Last August, Sodroski's group published an 11-Å version of the trimer online in Nature Structural & Molecular Biology, a resolution more plausible to Henderson and others. But when Henderson was later asked by the same journal to referee a paper describing the 6-Å trimer, he wrote an extensive critique. The PNAS paper, he says, is revised only slightly from the version he read. "I was shocked," Henderson says. "They completely ignored my five pages of critiques."

Hahn says she has yet to see an experiment that proves Sodroski and Mao made a mistake. "Ultimately," she says, "the biology has to decide who's right and who's wrong."

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