'Redesigned' antibodies may control HIV

May 18, 2015
HIV, the AIDS virus (yellow), infecting a human immune cell. Credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

With the help of a computer program called "Rosetta," researchers at Vanderbilt University have "redesigned" an antibody that has increased potency and can neutralize more strains of the AIDS-causing human immunodeficiency virus (HIV) than can any known natural antibody.

Their findings, published online today in The Journal of Clinical Investigation, suggest that computer-redesigned antibodies may speed the search for an effective therapy or vaccine for a virus that so far has eluded all attempts to eradicate it.

"There's a consensus (in the HIV field) that the vaccine that works is going to be a designed one," said James Crowe Jr., M.D., director of the Vanderbilt Vaccine Center who led the work with Jens Meiler, Ph.D., associate professor of Chemistry and Pharmacology.

Working with colleagues at The Scripps Research Institute in La Jolla, California, the Vanderbilt researchers began with a "parent" antibody isolated from the blood of an HIV-infected person that was a strong "neutralizer" of HIV in laboratory tests.

The researchers then used the Rosetta computer program, which can predict the structure of a protein from its amino acid sequence, to "redesign" the antibody. By changing a single amino acid, they were able to increase the stability of the antibody when it bound to HIV's envelope protein.

The researchers didn't change the interface between the antibody and the virus. Rather, by increasing its thermodynamic stability, the antibody became more rigid and better able to fit the HIV protein like a lock and key.

"By changing a single amino acid, we made it four times more potent, four times stronger and it also started killing even more HIV strains than the parent antibody," said Crowe, Ann Scott Carell Professor and professor of Pediatrics and of Pathology, Microbiology and Immunology.

The original, isolated antibody is now being produced in great quantities from a single clone of immune cells, and thus is a "monoclonal" antibody. It currently is being tested in clinical trials. Crowe said the redesigned antibody could be added to the study as a second-generation version.

The field of redesigning antibodies has grown quickly out of the need to treat and prevent debilitating and often-fatal viral infections, and from technological advances that have made it possible to "see" and strengthen the interactions between virus and virus-killing antibodies.

HIV is a wily opponent. Every day it evolves, or alters the envelope protein on its surface, to evade immune detection. A single person infected with HIV carries more variations of the virus than all the influenza strains isolated worldwide, Crowe said. The immune system simply cannot keep up.

In 2013, Scripps scientists led by Ian Wilson, Ph.D., and Andrew Ward, Ph.D., reported in the journal Science the structure of the HIV envelope protein using crystallography and cryo-electron microscopy. "Now we know what it looks like," Crowe said. "We can better understand how to target it."

Last year, Crowe and another colleague at Scripps, William Schief, Ph.D., reported in the journal Nature that "computational protein design" can be used to induce potent neutralizing antibodies of respiratory syncytial virus (RSV), a leading cause of respiratory infections in young children.

"That was the first paper in which people agreed that computer design of a vaccine worked," he said.

Structure and proof of principle in hand, scientists are now using the computer to generate neutralizing antibodies against parts of the envelope protein that don't change.

Down the road, Crowe said, "if computational design ... can predict how viruses evolve in the future, we could potentially design antibodies and vaccines for viruses before they occur in nature."

Toward that end, Crowe and Meiler have organized the Interface Group, a diverse collaboration of scientists across campus, including an expert in game theory who is modeling the interplay between viruses and the immune system.

"You couldn't have this type of biomedical research," he said, "without that playful, curious aesthetic sense that you get with the Rosetta 'community.'"

Explore further: Mechanism found for development of protective HIV antibodies

More information: Redesigned HIV antibodies exhibit enhanced neutralizing potency and breadth, J Clin Invest. 2015. DOI: 10.1172/JCI80693

Related Stories

Mechanism found for development of protective HIV antibodies

July 24, 2014
Scientists at Duke Medicine have found an immunologic mechanism that makes broadly neutralizing antibodies in people who are HIV-1 infected.

New research offers hope for HIV vaccine development

August 13, 2014
In a scientific discovery that has significant implications for HIV vaccine development, collaborators at the Boston University School of Medicine (BUSM) and Duke University School of Medicine have uncovered novel properties ...

Scientists discover HIV antibody that binds to novel target on virus

September 3, 2014
An NIH-led team of scientists has discovered a new vulnerability in the armor of HIV that a vaccine, other preventive regimen or treatment could exploit. The site straddles two proteins, gp41 and gp120, that jut out of the ...

Knowing origin of broadly neutralizing antibodies could aid universal flu vaccine design

August 29, 2012
National Institutes of Health scientists have identified how a kind of immature immune cell responds to a part of influenza virus and have traced the path those cells take to generate antibodies that can neutralize a wide ...

Scientists boost potential of passive immunization against HIV

August 13, 2014
Scientists are pursuing injections or intravenous infusions of broadly neutralizing HIV antibodies (bNAbs) as a strategy for preventing HIV infection. This technique, called passive immunization, has been shown to protect ...

Scientists create new tool for identifying powerful HIV antibodies

May 9, 2013
A team of NIH scientists has developed a new tool to identify broadly neutralizing antibodies (bNAbs) capable of preventing infection by the majority of HIV strains found around the globe, an advance that could help speed ...

Recommended for you

Scientists elicit broadly neutralizing antibodies to HIV in calves

July 20, 2017
Scientists supported by the National Institutes of Health have achieved a significant step forward, eliciting broadly neutralizing antibodies (bNAbs) to HIV by immunizing calves. The findings offer insights for HIV vaccine ...

Heart toxin reveals new insights into HIV-1 integration in T cell genome

July 20, 2017
Human immunodeficiency virus (HIV)-1 may have evolved to integrate its genetic material into certain immune-cell-activating genes in humans, according to new research published in PLOS Pathogens.

Scientists capture first high-resolution image of key HIV protein transitional state

July 13, 2017
A new, three-dimensional snapshot of HIV demonstrates the radical structural transformations that enable the virus to recognize and infect host cells, according to a new study led by scientists at The Scripps Research Institute ...

Barrier to autoimmune disease may open door to HIV, study suggests

July 11, 2017
Researchers from the University of Colorado School of Medicine have discovered that a process that protects the body from autoimmune disease also prevents the immune system from generating antibodies that can neutralize the ...

Team tests best delivery mode for potential HIV vaccine

June 20, 2017
For decades, HIV has successfully evaded all efforts to create an effective vaccine but researchers at The Scripps Research Institute (TSRI) and the La Jolla Institute for Allergy and Immunology (LJI) are steadily inching ...

Mathematical modeling uncovers mysteries of HIV infection in the brain

June 19, 2017
After uncovering the progression of HIV infection in the brain thanks to a new mathematical model developed by a UAlberta research team, clinicians and researchers are developing a nasal spray to administer drugs more effectively.

0 comments

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.