Why evolution is the challenge—and the promise—in developing a vaccine against HIV

December 1, 2017, Children's Hospital Boston

To fight HIV, the development of immunization strategies must keep up with how quickly the virus modifies itself. Now, Boston Children's Hospital researchers are developing models to test HIV vaccines on a faster and broader scale than ever before with the support of the Bill & Melinda Gates Foundation.

"The field of HIV research has needed a better way to the immune responses that happen in humans," says Frederick Alt, PhD, director of the Boston Children's Program in Cellular and Molecular Medicine, who is leading the HIV vaccine research supported by the Gates Foundation.

The researchers are racing against HIV's sophisticated attack on the human immune system. HIV, the human immunodeficiency virus, mutates much faster than other pathogens. Within each infected patient, one virus can multiply by the billions. This prolific replication creates endless opportunity for genetic mutations, some of which can enable the virus to avoid detection and attack by the patient's immune system.

With so many variants of the virus rampantly accumulating—and spreading—among people, HIV researchers have been hard pressed to find an immunization strategy capable of producing against HIV that are capable of "broadly neutralizing" diverse viral strains.

Yet we know that such a "magic bullet" exists. In rare cases, people infected with HIV are able to produce broadly-neutralizing antibodies on their own. Therein lies a tantalizing possibility—that a much more extensively-reaching, protective version of such an antibody could be induced in uninfected individuals through preventative immunization.

Bridging a gap from lab models to reality

Achieving this goal requires HIV researchers to take a whole new approach at eliciting broadly neutralizing antibodies in the laboratory. Mice—the most commonly used animal model for immunological studies like HIV research— are much, much smaller than humans. As a result, mice have far fewer immune cells called B cells, which are the cellular factories responsible for assembling antibodies and directing the immune system's attack on pathogens like HIV.

Thus, until now, working with mouse models of HIV has only allowed researchers to replicate a tiny percentage of the possible HIV antibodies that human bodies are capable of producing. What's more, it has been a slow process, reliant on mice's reproductive cycles.

"Conventionally, it has required the time-consuming breeding of multiple generations of mice to generate humanized models for testing how to elicit highly-evolved, highly-mutated HIV antibodies," says Alt.

So, Alt and his team developed a nimbler vaccine test system that could speed up natural "evolution" of human antibodies in mice.

Turning evolution against HIV

First, they engineered mouse embryonic stem cells so that they would rapidly develop into mice containing humanized versions of the genetic building blocks that B cells use to assemble antibodies. Then, partnering with collaborators at other institutions, the team immunized the mice with specially-designed HIV antigens, coaching their immune systems to produce increasingly varied antibodies. Some of these antibodies were eventually able to neutralize viral strains.

"Rather than go through generations of mouse breeding to make models, our approach allows us to quickly delete and replace genomic elements to create changes in B cells," Alt said in a Vector story about the advance. "Thus, we can rapidly re-program our mouse model with the intermediate antibody genes selected from the first successful immunizations, and expose them to new antigens. Over time, we hope this process will lead to a vaccine strategy that will elicit broadly neutralizing HIV antibodies."

It is a promising-enough strategy towards developing an HIV vaccine that the Gates Foundation is now investing in further enhancing Alt's mouse models. With the foundation's support, an essential piece is making the modified mice available to other major HIV research teams, further speeding the search for ways to induce broadly-neutralizing antibodies against HIV.

"The foundation is setting up ways to distribute our models and providing funds for investigators to use them and collaborate with us on collective next steps in this field of research," says Alt. "It's set up as a system that supports people who receive the model, insuring that they can do their part. A big team effort such as the Collaboration for AIDS Vaccine Discovery is the only way we will find a way to combat HIV—a research consortium like this is a great way to go after a disease."

Explore further: New mouse model technology could speed the search for an AIDS vaccine

Related Stories

New mouse model technology could speed the search for an AIDS vaccine

September 8, 2016
Researchers at Boston Children's Hospital have developed a technology to quickly generate mouse models for testing and tweaking potential HIV vaccines. Such models could speed up the quest for the AIDS field's "holy grail"— ...

Training human antibodies to protect against HIV

September 8, 2016
During HIV infection, the virus mutates too rapidly for the immune system to combat, but some people produce antibodies that can recognize the virus even two years after infection. With an eye towards developing a vaccine, ...

Researchers find alternative pathways to HIV antibodies

May 4, 2016
The immune system appears to hamper an investigational vaccine from inducing antibodies that protect against HIV infection, but there may be ways to overcome this impediment, according to research led by the Duke Human Vaccine ...

Antibody combination puts HIV on the ropes

January 25, 2017
Without antiretroviral drug treatment, the majority of people infected with HIV ultimately develop AIDS, as the virus changes and evolves beyond the body's ability to control it. But a small group of infected individuals—called ...

Researchers uncover clues about how HIV virus mutates

June 1, 2017
A new study published in Cell Host & Microbe led by researchers at Fred Hutchinson Cancer Research Center completely maps all mutations that help the HIV virus evolve away from a single broadly neutralizing antibody, known ...

Researchers map pathways to protective antibodies for an HIV vaccine

March 15, 2017
A Duke Health-led research team has described both the pathway of HIV protective antibody development and a synthetic HIV outer envelope mimic that has the potential to induce the antibodies with vaccination.

Recommended for you

Study shows how HIV is shielded from immune attack

July 10, 2018
Scientists from UNSW Sydney and the UK have discovered that the human immunodeficiency virus (HIV) hijacks a small molecule from the host cell to protect itself from being destroyed by the host's immune system.

Out-of-pocket costs put HIV prevention drug out of reach for many at risk

July 4, 2018
Public health officials are expanding efforts to get the HIV prevention pill into the hands of those at risk, in a nationwide effort to curb infections. But the officials are hitting roadblocks—the drug's price tag, which ...

New simulation tool predicts how well HIV-prophylaxis will work

June 14, 2018
A new mathematical simulation approach predicts the efficacy of pre- and post-exposure prophylaxis (PrEP) medications, which help prevent HIV infection. The framework, presented in PLOS Computational Biology by Sulav Duwal ...

Many at risk for HIV despite lifesaving pill

June 11, 2018
Multiple barriers may stop high-risk individuals from accessing an HIV drug that can reduce the subsequent risk of infection, according to a new University of Michigan study.

Active HIV in large white blood cells may drive cognitive impairment in infected mice

June 7, 2018
Macrophages, large white blood cells that engulf and destroy potential pathogens, harbor active viral reserves that appear to play a key role in impaired learning and memory in mice infected with a rodent version of HIV. ...

HIV vaccine elicits antibodies in animals that neutralize dozens of HIV strains

June 4, 2018
An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.