After nearly three decades of grappling to understand a virus that consistently changes form, Duke researchers have mapped out a course for developing an HIV vaccine.
The development of an HIV vaccine has proved one of the most difficult medical feats in history because the virus mutates quickly and often once it enters the body. Duke researchers, however, have gained a new understanding of HIV by charting for the first time the evolution of the virus, as well the evolution of antibodies created in response to the mutating virus after it enters the body.
Although most individuals’ immune systems are unable to create antibodies that can neutralize the consistently changing virus, the researchers found a small subset of infected people whose immune system creates broadly neutralizing antibodies, which are able to attack parts of the virus that do not change overtime.
By discovering and studying the broadly neutralizing antibodies, the researchers could evaluate ways to induce these antibodies in infected individuals. The researchers were successful in finding an immunogen—a substance that provokes an immune system response—able to induce these antibodies.
These findings were published in the science journal, Nature, April 3.
“What the Nature paper does for the first time is it shows the arms race from the antibody point of view and the virus point of view,” said Dr. Barton Haynes, leader of the research team and director of the Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery. “We have the sequence of [HIV] mutations that induce the broadly neutralizing antibodies. The black box is open.”
The ‘arms race’
Most individuals’ immune systems do not create broadly neutralizing antibodies. As the virus evolves over time, the immune system creates different antibodies to respond to each “new” version of HIV.
“The best way to think about the problem is an arms race—when one country makes a bomb and another country makes a bigger bomb and it goes back and forth,” Haynes said. “It goes back and forth and in most people it does not result in broadly neutralizing antibodies, it ends up in poorly or very narrowly restricted neutralizing antibodies.”
Frequently, the antibodies have undergone so many mutations to fight the evolving virus that they have genetic defects, causing the immune system to dispose of them.
“Most of these antibodies go down these long pathways and never make it,” Haynes added.
Broadly neutralizing antibodies differ from most antibodies in that they are able to latch onto areas on the virus that do not change over time—these are called “conserved regions.”
The researchers found, however, that broadly neutralizing antibodies are not only rare, but very complex.
Broadly neutralizing antibodies only exist in 20 percent of patients infected with HIV and take three to four years to develop naturally in those individuals.
Additionally, the broadly neutralizing antibodies have certain traits that make them susceptible to tolerance mechanisms, the processes by which the immune system removes or inactivates the antibodies.
For example, broadly neutralizing antibodies bond to a particularly long region of HIV, which in turn can cause them to react with tissue. Because the antibodies will react with human tissue, the immune system views the antibodies as invaders, causing them to be eliminated through tolerance mechanisms.
As a result, Haynes and his research team had to look for broadly neutralizing antibodies that are not as susceptible to elimination by tolerance mechanisms.
“We need to know if there are broadly neutralizing lineages that are more normal because we don’t want to induce the weird antibodies,” he said.
‘The vaccine is possible’
After seeing the importance of finding the “normal” lineages of broadly neutralizing antibodies, Haynes’ research team set out to find less complicated broadly neutralizing antibodies that come up early in infection.
Dr. Feng Gao, an author on the study and an investigator at CHAVI, noted that it is important to induce several of these antibodies in order to neutralize the virus most effectively. He added that this is akin to a patient taking the “cocktail,” a mixture of antiretroviral drugs, each of which target a different area of HIV.
“When you put a number of drugs together they each target a different area [of the virus] and resist the virus very well,” Gao said. “It’s the same idea with vaccines—if you are targeting multiple [antibodies] than the vaccine will be more potent than if you were targeting just one.”
The research team was successful in sequencing broadly neutralizing antibodies that promise to be effective in neutralizing HIV because they are not at risk for elimination by the immune system.
“What we found here are some rare antibodies that don’t bind to tissue and don’t have a lot of weird traits, but there are very few of them,” Haynes said.
As a result, the researchers are now looking to induce three types of broadly neutralizing antibodies to neutralize HIV, Haynes said.
Dr. Larry Liao, lead author of the study and director of research at the Duke Human Vaccine Institute, noted how finding broadly neutralizing antibodies holds great potential for the development of a vaccine.
“If you have broadly neutralizing antibodies induced in the body… we will have much more of a chance to kill that virus,” said Liao, who is also an investigator at CHAVI. “Based on this, the vaccine is possible.”
The researchers have found an immunogen that is capable of inducing such antibodies, which is the envelope of the original virus that started the individual’s infection.
The next step for the researchers is to pick several of the already sequenced broadly neutralizing antibodies, selecting for the ones that bind to HIV the best, and start testing on animals, Haynes said. Testing on humans should occur thereafter.
From this point on, it is only a matter of time before this roadmap is turned into a vaccine. How much time, however, remains unknown.
“We know exactly how [broadly neutralizing antibodies] are induced because the infected individuals have taught us this, which has showed us a roadmap to win the arms race,” Haynes said. “ As for timing? Who knows.”
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