Illustration by Kim Carney / Fred Hutch News Service
Forward progress sometimes requires a backward glance. A twenty-five-year-old blood sample from an infant infected with HIV could hold clues to modeling a better HIV vaccine, according to work published in Nature Communications by scientists at Fred Hutchinson Cancer Research Center.
The sample, which held a special HIV-blocking protein that can develop after HIV infection, was taken during a groundbreaking HIV transmission trial conducted in the early 1990s. At the time antiretroviral drugs were not available and whether HIV could be transmitted through breast milk was unknown. HIV-positive mothers in Nairobi, Kenya, helped researchers discover that the virus could indeed spread to infants via breastfeeding. Carefully preserved for more than two decades, the blood samples collected during this study are providing new answers to then-undreamed-of questions made possible by advances in research tools.
The special HIV-blocking protein in the infant’s blood is known as a broadly neutralizing antibody. HIV vaccine developers hope that vaccines that trigger this protein prior to HIV exposure — a goal that has yet to be achieved in people — can protect people from HIV infection.
After tracing the antibody’s evolution using new computational methods, the Hutch scientists found that it had taken a shortcut compared to broadly neutralizing antibodies from people infected with HIV as adults.
“This is basic science information that will inform how we could think about designing a vaccine,” said Fred Hutch HIV researcher Dr. Julie Overbaugh, the study’s senior author.
Antibodies: an evolving shield against infection
Antibodies are protective proteins that are released into the body by immune cells called B cells. Antibodies recognize and bind specific parts of germs called antigens. Some antibodies protect us by blocking, or neutralizing, a germ’s ability to infect. Those that can block infection by many variants of HIV are called broadly neutralizing antibodies.
Photo by Robert Hood / Fred Hutch News Service
Historically, effective vaccines have mimicked the immune response to a natural infection by using some piece of a germ to trigger the body to produce antibodies against it. Since HIV was discovered nearly 40 years ago, researchers have dreamed of developing a similarly protective vaccine. The best attempt so far, called the Thai trial or RV 144, only reduced infection rates by 31% in people who had been vaccinated compared to those who had not. Several other HIV vaccines are currently being tested for their ability to prevent HIV infection, including two in trials being conducted by the HIV Vaccine Trials Network, headquartered at Fred Hutch.
One way to create a vaccine that triggers broadly neutralizing antibodies is to work backward from broadly neutralizing anti-HIV antibodies found in people. But it’s more complicated than merely finding the right antibody, figuring out what it “sees” on HIV, and sticking this portion of HIV in a vaccine: Our antibodies change over the course of an infection.
During an infection, a B cell whose antibody bound the infecting microbe will revise the DNA sequence containing the instructions for making that antibody, so it becomes more effective and binds its target more strongly.
So vaccine developers hoping to recreate a broadly neutralizing antibody seek out its starting point, the original antibody that responded to the infection, said Overbaugh, who holds the Endowed Chair for Graduate Education. Most studies have focused on broadly neutralizing antibodies from HIV-positive adults. These antibodies can take up to a decade to develop. Vaccines need to protect much more quickly.
Instead, Overbaugh and her team looked to infants, which they already knew could produce broadly neutralizing antibodies within months of infection.
Photo by Colin Petersdorf / Fred Hutch News Service
Tracing a fast-acting response
Overbaugh and co-first author Dr. Cassandra Simonich, then a graduate student in Overbaugh’s lab, had already shown that in one infant, a broadly neutralizing antibody developed in less than a year after the child was infected by HIV through breast milk.
To improve their understanding of how the antibody developed so quickly, Simonich, postdoctoral fellow Dr. Laura Doepker and Overbaugh decided to recreate the original antibody as it existed prior to its genetic rejiggering. To do so, they worked with Hutch colleague and computational biologist Dr. Frederick Matsen to create bespoke computational approaches to reconstruct the original antibody.
The study is “novel in terms of really using robust computational methods that were designed specifically for this problem,” said Overbaugh.
Mapping the path
When the researchers reconstructed the antibody’s original, “naïve” state, two characteristics stood out: how little it had changed, and what it binds.
Just 2% of the antibody’s gene sequence had to be altered to generate the broadly neutralizing antibody. That’s a mere fraction of the genetic alteration undergone by the average adult broadly neutralizing antibody, which may have revised up to 25% of its original gene sequence.
“That was really impressive,” Overbaugh said.
For unclear reasons, many previously reconstructed naïve antibodies don’t actually bind HIV, making them nonstarters for vaccine developers hoping to work backward to an immune-triggering vaccine, she noted.
In contrast, the infant’s reconstructed naïve antibody does bind HIV, which means that a fragment of HIV that binds this or a similar antibody could theoretically form the basis of a vaccine that stimulates a broadly neutralizing response that is similar to the one made by the infant.
“This is a showstopper, I think, for some of these B-cell lineages that [vaccine developers] want to hit,” Overbaugh said.
A first step
The team doesn’t yet know why the antibody developed so quickly with so little reworking. Is it something special about that variant of HIV? Something special about the original antibody, or something about the infant immune system in general? It’s also too soon to know if this short evolutionary path is a hallmark of infant responses to HIV, or merely unique to this individual infant.
“We’d like to know whether this just happened to be a one-off, or whether it’s a more common feature of infants,” Overbaugh said, cautioning against extrapolating too far from a single antibody in a single infant. The current findings arising from decades-old tissue samples is a testament to the value of long-standing collaboration and scientific foresight, she said.
Her team is examining antibodies from other infants whose mothers participated in the breastfeeding study to determine if the infant immune system follows a common antibody-generating pathway to broadly protective antibody responses via minimal genetic manipulation. More work also needs to be done to determine whether similarly quick-acting, broad antibody responses could be triggered in adults.
If so, the generosity of Kenyan women 25 years ago could tie this infant’s immune response to improved HIV protection for all.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.
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