Nailing down Env in HIV

TSRI research details newly discovered binding sites for HIV antibodies

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LA JOLLA, Calif.—The Scripps Research Institute (TSRI) has released results from a trio of studies into HIV that have revealed new targets and insight into the potential of broadly neutralizing antibodies.
HIV has always been difficult to treat given its ability to evade the immune system. The virus infects healthy cells via envelope protein (Env) structures, which are found on its viral membrane, that grab and penetrate host cells. While the Env structures are HIV’s most vulnerable parts, the virus can cover the structures with rapidly mutating decoy proteins and glycans, which are antibody-resistant sugar molecules. Research has uncovered only a few sites on Env where protein and glycan structures are less prone to change, given that they play roles in crucial viral functions.
Back in April, the institute announced results of research that, led by TSRI scientists working with the International AIDS Vaccine Initiative (IAVI), detailed the discovery of a vulnerable site on the HIV virus where human antibodies can neutralize the infective capabilities of a range of HIV strains. Two papers—one headed by TSRI Prof. Dennis Burton and the other by TSRI Assistant Prof. Andrew B. Ward and Ian A. Wilson, Hansen Professor of Structural Biology—were published in the May issue of Immunity. Burton is a professor in TSRI’s Department of Immunology and Microbial Science and scientific director of the IAVI Neutralizing Antibody Center (NAC) and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) on TSRI’s La Jolla campus. Wilson is chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI, and he and Ward are both also members of the NAC and CHAVI-ID. This research is part of an effort sponsored by the NIH and IAVI to develop an HIV vaccine.
Previously, scientists had only identified a few sets of broadly neutralizing antibodies that could reach four conserved vulnerable sites on the HIV virus, all of which are found on the Env protein (gp140) that sprouts from the viral membrane.
The team tested blood samples from IAVI Protocol G, in which IAVI and its NAC worked with clinical research centers in Africa, India, Thailand, Australia, the United Kingdom and the United States to collect blood samples from more than 1,800 healthy, HIV-positive volunteers to identify rare, broadly neutralizing antibodies. Serum from a small number of samples proved capable of blocking, in test cells, the infectivity of a variety of HIV isolates. In 2009, scientists from IAVI, TSRI and Theraclone Sciences isolated and characterized the first new broadly neutralizing HIV antibodies seen in 10 years.
Emilia Falkowska—a research associate in the Burton laboratory and a key author of one of the papers—and colleagues found a set of eight closely related antibodies responsible for most of one of the sample’s HIV-neutralizing activity. The discovery was detailed in the paper “Broadly neutralizing HIV antibodies define a novel glycan-dependent epitope on the pre-fusion conformation of gp41 on cleaved Envelope trimers.” It was determined that the two broadest neutralizers in the set, PGT151 and PGT152, were capable of blocking the infectivity of roughly two-thirds of a panel of HIV strains found worldwide.
Despite that ability, the antibodies didn’t bind to any previously described sites on Env or anywhere on purified copies of gp120 or gp41, two Env protein subunits. Further research revealed that PGT151 and PGT152 do not bind to gp120 or gp41 individually but to parts of both—gp120 and gp41 assemble into an Env structure as a trimer, and PGT151 and PGT152, as it turns out, have a binding site that occurs only on a mature Env trimer structure.
“These are the first HIV neutralizing antibodies we’ve found that unequivocally distinguish mature Env trimer from all other forms of Env,” said Falkowska. “That’s important because this is the form of Env that the virus uses to infect cells.”
The second study, “Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers,” provided an initial structural analysis of the new vulnerable epitope. Through combining electron microscopy on the Env trimer complex with PGT151 (led by the Ward lab) with the structure of the PGT151 Fab by X-ray crystallography (led by Wilson’s lab), the scientists managed to visualize the location of the PGT151-series binding site on the Env trimer. Said location includes a spot on one gp41 protein with two associated glycans, a patch on the gp120 protein and a piece of the adjacent gp41 in the trimer structure. Equally surprising was the discovery that the way the PGT151-series antibodies bind to the Env trimer actually stabilizes its structure.
In a third study—“Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV”—Burton led a team in investigating another vulnerable site on Env that is known as the “high-mannose patch” given the frequency of molecules, known as mannoses, on its glycans. The high-mannose patch on Env is found on a glycan attachment point known as N332. Previous work has suggested that HIV can mutate in a way that shifts the glycan from N332 to N334, thereby “escaping” a broadly neutralizing antibody, but Burton’s team found that many N332-targeted antibodies are still capable of neutralizing the virus even when it employs this defense by grabbing other glycans in the high-mannose patch.
This suggests that a broadly neutralizing antibody targeting the high-mannose patch might not have one defined target, but instead could find several ways to bind to available glycans and neutralize the HIV virus. It is possible that just targeting the high-mannose patch with diverse types or clones of antibodies could neutralize as much as 90 percent of viral isolates and block most avenues of viral escape.
The high-mannose patch is a challenge to target, says graduate student Devin Sok, one of the lead authors of the study, because while it is an immunogenic site that is commonly targeted in individuals who develop broadly neutralizing antibodies in the face of chronic infection, “a sugar epitope is very challenging to mimic for immunogen design because the sugars tend to move around a lot, so it’s hard to lock down their conformation.” In addition, he adds, antibodies tend to bind poorly to sugars.
While existing retroviral HIV therapies work by targeting different pathways of HIV’s life cycle, Sok says their hope is “to prevent the acquisition of the disease entirely, by eliciting these broadly neutralizing antibodies in healthy individuals using carefully designed immunogens. Our work demonstrates high promise for broadly neutralizing antibodies targeting a specific patch of sugars on HIV.”
This approach isn’t solely applicable to HIV either, he says, as there is potential for applying this method to other viruses such as influenza and HCV.
Sok says the team will continue to “isolate new antibodies that target this patch of glycans to better decipher the details of this epitope,” while also investigating how to solicit similar antibodies in healthy individuals.

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