Wednesday, September 20, 2017

New clues to making an effective HIV vaccine found by Scripps Research scientists

Bradley J. FikesContact Reporter

Powerful antibodies against HIV bind to a key site on the deadly virus, helping the immune system “learn” how to neutralize it, a team led by scientists at The Scripps Research Institute report. The discovery may help guide development of a vaccine.

The study was published Sept. 12 in the journal Immunity. Raiees Andrabi was first author. Dennis Burton, a longtime expert on HIV antibodies, was senior author. Go to for the study.

The site bears a patch of sugars called glycans. This patch fixates the immune system’s attention, helping it produce potent antibodies that neutralize a broad range of HIV strains. But in nature the process takes too long to be of much use. That’s what scientists at Scripps Research and elsewhere are trying to fix with a vaccine.

HIV makes glycans from the cells it infects, wearing them as shields that disguise the virus from the immune system. This glycan shield is one reason HIV is so hard to defeat. The other is that HIV mutates prodigiously, so it quickly escapes from antibodies that work against just one strain.

By the time broadly neutralizing antibodies are finally produced, the virus has got a firm foothold and worn down the immune system.

Scientists at The Scripps Research Institute and elsewhere have worked for decades to discover these broadly neutralizing antibodies, found in the blood of some HIV-positive people. They generated much excitement when first found, demonstrating that HIV is not as invulnerable as it originally appeared.

Their discovery inspired research to engineer an HIV vaccine that quickly produces broadly neutralizing antibodies. Such a vaccine might be capable of stopping the virus in tracks, preventing an infection from taking hold.

The bovine immune system is especially adept at making vaccines for this human disease. HIV doesn't infect cows.

So for more than two decades, scientists at TSRI and elsewhere have been learning everything they could about broadly neutralizing antibodies, examining where they attach to the virus, how they work together, and what features of the immune system are involved in making them.

Previous studies have shown that the immune system is incapable of making broadly neutralizing antibodies when first exposed to HIV. Immune cells must be progressively led down the path to make the antibodies. So it appears that no vaccine can produce immunity in one step; a series of vaccinations will be required.

In the new study, researchers examined an especially powerful family of broadly neutralizing antibodies, called CAP256.VRC26. They found that the site anchored these antibodies in the early stages of immune response development, and helped the immune system keep its focus even as HIV mutated.

Ajit Varki, a prominent glycobiologist and physician-scientist at UC San Diego, said the discovery is part of a series of major advances from the Scripps Research team.

The idea that a cluster of glycans might form an identifiable handle has been around for some time, Varki said.

“However, the outstanding series of papers on this topic from the TSRI group (of which this is the latest) is the first example to my knowledge where this concept is visualized in structural detail,” Varki said by email.

“What appears most novel is that unlike the previous studies, the glycans involved here terminate in a common form of human sugar called sialic acid. While there are potentially important details missing such as the impact of different kinds of sialic acids, this does not take away from the important finding that these antibodies are capable of neutralizing the HIV virus specifically, and could be potentially developed into therapeutics."

Varki cautioned that exploiting this discovery could be “tricky,” because the glycans appear similar to those on normal human cells.

“What makes it unique is the unusual clustering induced by the HIV protein,” Varki said. “So one would need to be sure not to induce cross-reactive antibodies during immunization."

The research was funded by the International AIDS Vaccine Initiative, the National Institute of Allergy and Infectious Diseases, the Ragon Institute, the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery, and the U.S. Agency for International Development.
For further reading

In struggle against HIV, scientists get help from cows

Scientists inching ever closer to HIV vaccine

Most powerful HIV- attacking antibody yet has been constructed

Stripped-down HIV antibodies could make better vaccine targets

HIV vaccine trial set for next year

AIDS Researchers Find 17 New, More Potent, Broadly Neutralizing Antibodies


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