Harnessing Antibodies to Protect Against HIV Infection

HIV is hard to combat because of its ability to evade the immune system, but some individuals are able to produce antibodies that can recognize the virus, even years after infection.

In 4 related papers published in Cell and Immunity conducted by several groups, researchers relayed a multi-step method for training the immune system to produce these antibodies in genetically engineered mice.

PGT121 antibodies are able to recognize different iterations of the virus, but when they are produced naturally, they don’t have enough juice to cure the systemic infection. However, according to researchers, they may be strong enough to prevent the infection if induced by a vaccine.

“They are not capturing only the first or second version of the virus that they ran into,” said co-senior author of 2 of the studies, Michel Nussenzweig. “They retain the ability to catch all of the virus mutations they’ve seen before.”

As a conceptual test, Nussenzeig’s group developed a way to train the immune system to produce the PGT121 antibodies that react to diverse strains of HIV, using mice that were genetically engineered to simulate the immune system.

Since the immune system contains numerous different precursors, only a few of which could give rise to the antibodies, researchers had to genetically analyze the antibodies in order to determine what their native state most likely was.

Next, they created a series of viral protein structures that could eventually teach the antibodies to recognize multiple forms of the natural HIV. Researchers started from HIV and worked backwards, and this stage of work was led by immunologist and co-senior author William Schief.

“The antibody precursors, or what we estimate as their precursors, don’t seem to have detectable affinity themselves for the virus,” Schief said. “We need to convert HIV into something stable that would kick start the process.”

The development of these structures is highlighted in the Immunity paper. Nussenzeig’s group continued on to test the iterative training process by using genetically engineered mice, which only produced the human precursors that could generate PGT121 antibodies.

First, researchers started with the first synthetic immunogen developed by Schief that could bind the PGT121 precursor. They tested the mouse serum to see if any antibodies had also reacted to the next immunogen in the sequence.

The experiment was a success, with researchers able to mature a broadly neutralizing antibody in the mice that mimicked those found in individuals with HIV. Authors noted that the work only offers a conceptual framework to develop a vaccine, and not the vaccine itself.

“We have done this in a very contrived mouse model,” Nussenzweig said. “In a normal mouse – or a normal human – the immune system has a huge repertoire, and the antibody precursors that we’re looking for are only a small fraction. If we put the same initial immunogen in a wild-type animal, it’s very unlikely that enough of the immunogen would find the right precursors to get the whole thing started.”

Despite this, the findings are another step in the journey to find an HIV vaccine.

“You have to start somewhere,” Schief said. “This is a big step forward – we have shown that it’s possible to guide antibody maturation from a human germline to produce broadly neutralizing antibodies by vaccination.”

The next step in the process will be to develop immunogens that have a high affinity for antibody precursors that are present in humans. If this is achieved it will allow the vaccine to locate and train the right parts of the immune system in humans.

In a related study published in Cell, researchers demonstrated how to quickly generate a humanized mouse model for testing new HIV vaccine strategies. The B cells assembled a highly diverse set of HIV antibody precursors in their mouse model that can be taught to produce humanized antibodies that can neutralize some HIV viral strains.

“Rather than go through generations of mouse breeding to make models, our approach allows up to quickly delete and replace genomic elements to create changes in B cells,” said co-senior study author Fred Alt. “Thus, we can rapidly re-program this mouse model with the intermediate antibody genes selected from the first successful immunizations and expose them to new antigens. We’re hoping it will be broadly useful.”

Still, authors note that more research needs to be done.

“We need to further understand how to engender optimal antibody affinity maturation to evolve the antibody response toward effective virus neutralization,” said co-senior study author John Mascola. “But these types of questions can be partially addressed in our humanized mouse models, to help select vaccine antigens and immunization strategies for phase 1 human studies.”

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