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Custom proteins can help create antibodies to fight HIV


HIV infecting a human cell. Credit: NIH

A new way to create proteins capable of sneaking through the protective lining of HIV could be a step towards understanding the key components needed to develop a vaccine against the virus, according to the researchers.

Using computer modeling, a team of researchers led by Penn State has designed and created proteins that mimic different surface features of HIV. After being immunized with the proteins, the rabbits developed antibodies capable of binding to the virus.

"We were able to show that by using our designed proteins, the blood was able to spontaneously generate antibodies that could inhibit HIV infection in cell models," said Cheng Zhu, postdoctoral researcher at Penn State College. of Medicine. "When we incubated the HIV virus, its infectivity was greatly reduced by the blood of rabbits."

Zhu added that the study – published today (February 27) in Nature Communications-Provides a new way of designing proteins for vaccines.

"The proteins – or immunogens – that we have developed are not a finished product, but we have been able to demonstrate that it was possible," Zhu said. "In addition, it is also very interesting to be able to create a new method to customize proteins, which could also allow to develop vaccines against other infections."

Although millions of people are living with HIV around the world, the creation of a vaccine against the virus has alluded to researchers. Vaccines work by teaching the immune system where an antibody can attach to a virus before neutralizing it. To create a vaccine, researchers must first identify this place.

Nikolay Dokholyan, Professor G. Thomas Passananti and Vice President of Research at Penn State's Department of Pharmacology, explained that it is difficult to develop an HIV vaccine because the virus is undergoing constant mutation.

"Even if we develop an antibody for a particular strain of the virus, that antibody might not even notice the next strain of the virus," said Dokholyan. "In order to develop large neutralizing antibodies, antibodies that neutralize several strains of a virus, we have to find something that remains constant in the virus so that these antibodies can hang on."

According to Dokholyan, HIV uses a carbohydrate envelope to protect a protein on its surface called Env. Although this protein may be a potential target for vaccines, the carbohydrate coating makes it difficult, if not impossible, to access and neutralize antibodies.

But sometimes, holes appear naturally in this coating, exposing the Env protein to potential antibodies. Zhu said he and the other researchers wanted to find a way to target these holes.

"The idea would be to do molecular surgery to copy sections of the virus's surface and stick them on different benign proteins, so that they look like Env protein, but do not behave like them" Zhu said. "Hopefully this would allow the immune system to recognize the virus and create antibodies to neutralize it in the future."

The researchers used computer models to design proteins that mimic the conserved protein surface of different HIV strains for use in the vaccine. Dokholyan said that while proteins are usually made by modifying one amino acid at a time, they wanted to try a different approach.

"Instead of changing one amino acid at a time, it's a large area of ​​the HIV strain that is cut off and then inserted into a different protein," said Dokholyan. "This is an important step to perform these major molecular surgeries, and it is very interesting that the strategy works with great precision."

After creating immunogens using the new HIV-mimicking proteins, the researchers immunized the rabbits and took blood samples once a month. After analyzing the samples, the researchers found that the blood contained antibodies that could bind to HIV.

The researchers said that while the results are promising, there is still a lot of work to be done.

"It's important that we can generate an immune response to HIV and show that it's a possible proof of concept," said Dokholyan. "But we still need to improve the neutralization capabilities of antibodies and other aspects before they become a viable vaccine."

Dokholyan said that in the future, the protein design method could potentially help to create and customize vaccines for different diseases in different parts of the world.

"Diseases can vary from one place to another, for example, there are different strains of HIV in different countries or regions," said Dokholyan. "If we can easily customize the proteins for the vaccines, it's a good example of the place that personalized medicine will play."

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Custom proteins can help create antibodies to fight HIV (27 February 2019)
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