An atlas of HIV’s ‘escape routes’ could improve vaccine design

Electromicrograph showing an HIV-infected T cell in blue and yellow
HIV vaccine design has largely focused on proteins in the "envelope" that shuttle the virus into cells. (NIAID)

One of the reasons HIV infection is so hard to prevent and treat is that the virus mutates in order to evade broadly neutralizing antibodies—the immune system’s primary defense against viral pathogens. So scientists at the Fred Hutchinson Cancer Research Center constructed an atlas of HIV mutations, providing insight that they believe will boost the ongoing search for an effective vaccine.

The group showed that mutations can occur in the HIV “envelope,” a layer of glycoproteins that shuttle the virus into host cells and that interact with antibodies, even in places that those antibodies can’t reach. Their findings were published in the journal Immunity.

Developers of HIV treatments and vaccines have largely focused on the viral envelope, studying the sites where the outside proteins interact with neutralizing antibodies. Some drug makers have developed vaccines aimed at triggering broadly neutralizing antibodies, but with limited success.

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“In these immunotherapy clinical trials, there’s been viral escape from each antibody, and it’s critical to understand how that escape occurs,” said Adam Dingens, a graduate student who led the project at Fred Hutch, in a statement.

Dingens focused his research on “functional epitopes,” which are the areas of neutralizing antibodies that affect their ability to block HIV. He used a technology called deep mutational scanning to create a library of viruses with all the possible mutations that can occur in the gene that encodes HIV’s envelope protein.

By running all the mutated viruses through “a gauntlet of broadly neutralizing antibodies,” the team was able to observe how each mutation affected their ability to escape the immune attack, according to the statement. With further research, the scientists pinpointed the areas of the structural epitope that contribute to the neutralizing antibodies’ ability to block HIV.

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Broadly neutralizing antibodies remain an area of intense focus in HIV research. Last September, scientists at Rockefeller University released data from a phase 1b trial in which they combined two broadly neutralizing antibodies into an HIV treatment that they believe could be given to patients one or two times a year, freeing them from their daily pill regimen to control the virus.

Scientists at the International AIDS Vaccine Initiative (IAVI) and the Scripps Research Institute have studied HIV patients who have the innate ability to produce broadly neutralizing antibodies, in the hopes of applying what they learn to the design of new vaccines.

The Fred Hutch team believes researchers will be able to use their atlas to design new therapeutics, by choosing the antibodies for which HIV has limited “escape routes.” They also believe Dingens’ technique could be applied to other viruses, such as influenza, which is also the subject of research centered around developing vaccines that trigger broadly neutralizing antibodies.

“The atlas allows us to better understand the relationship between structure and function” of epitopes, Dingens said.

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