New HIV vaccine candidate discovered with help from Argonne’s Advanced Photon Source

By Jared Sagoff

Though not a full vaccine yet, discovery shows important proof of concept that can neutralize a third of the strains of HIV in the U.S.

The human immunodeficiency virus (HIV) is one of the most common and deadly viruses known to mankind. Approximately 40 million people around the world are living with HIV, and tens of millions worldwide have died from AIDS — the condition HIV leads to as it progresses — since the epidemic began in the early 1980s.

Although there are currently available antiretroviral medications for HIV, the silver bullet for it does not yet exist: an HIV vaccine. Scientists have been working on an HIV vaccine for a number of years but have had very limited success because the virus mutates so rapidly.

Recently, however, a group of scientists at Duke and Harvard Universities have conducted a study that may show new promise for a potential HIV vaccine. Their vaccine produces antibodies that are broadly neutralizing against more than a third of the strains of HIV present in the U.S. 

“Argonne, with the APS Upgrade, is now one of the most modern facilities in the world for protein science.” — John Rose, University of Georgia, director of SER-CAT

To assist in the development of this vaccine candidate, protein crystallography was performed at the SER-CAT (SouthEast Regional Collaborative Access Team) beamline 22-ID. The beamline was part of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory.

A vaccine works by using a small bit of biological or chemical material, called an antigen, that is designed to provoke the body’s immune response. This antigen can be a bit of genetic material, perhaps from the virus itself, although in other cases it can be something like bacteria. The body’s immune response consists of proteins called antibodies which work to combat the antigen.

“What is it about the immune system that can protect you from infection? You take a small piece, whether that’s a piece of the actual bug, or a weakened bug, or an attenuated bug, or a synthetic piece, like we did in this study, to stimulate the immune system and make it think it’s seen the bug before,” said Barton (Bart) Haynes, Frederic M. Hanes professor of medicine and immunology at Duke University and director of the Duke Human Vaccine Institute.

HIV is different from every other vaccine-capable disease — like measles, mumps, rubella, polio or tetanus — because it actually attacks what Haynes called the ​“orchestra director” of the entire immune system: the CD4 T-cell.

“Also, unlike all those other viruses, HIV inserts its genetic material into our own genetic material when it infects, and it can hide in cells from the immune system,” Haynes said. 

With other vaccines, according to Haynes, there isn’t need for total 100% protection, because the body can still have an adequate immune response even if infection occurs. With HIV, which can take over the entire immune system in a matter of a couple of days, it’s necessary to completely prevent infection.

“If even one infectious virion, or virus particle, gets into your system, it’s pretty much game over,” Haynes said. ​“One of the main reasons we don’t have an HIV vaccine right now is that the bar is much higher than for any other vaccine.”

To make a potential vaccine, Haynes and his colleagues designed a vaccine candidate that stimulates the production of broadly neutralizing antibodies, which are a somewhat dormant type of antibody that reside in the body but are only typically expressed over long periods of time.

There is a problem with making broadly neutralizing antibodies at first — because for HIV, the body’s antibodies look so similar to the body’s own cells, the body doesn’t want to make them for fear of triggering an autoimmune response.

“We’re having to teach or engineer the immune system to make an antibody that it doesn’t want to make,” Haynes said.

“The key to studying the structure of the antibody-virus combination is to stabilize the envelope protein to allow the antibody to attach to it,” said John Rose, associate professor of biochemistry and molecular biology at the University of Georgia and director of SER-CAT.

Haynes and his colleagues isolated a wide range of broadly neutralizing antibodies and created a roadmap of their genetic evolution from ​“naïve” antibodies where antibody lineages start, to mature antibodies that have a tight ​“lock and key” fit with the HIV virus’s protein envelope.

“We’re teaching antibody B cell lineages by saying, ​‘Hey, here’s what you’ve got to recognize on the HIV protein envelope, and you’ve got to join the fight,’” Haynes explained.

Haynes said that the process of getting the antibodies to have better binding to the HIV envelope is shaping a key for a lock.

“With the lock and key, you’re going from a blank key to introducing additional notches until you get a perfect fit,” he said.

The researchers targeted a region of the virus called the membrane-proximal external region (MPER), which is vulnerable to antibody attack and engagement, said Gilad Ofek, an assistant professor in the Department of Cell Biology and Molecular Genetics at the University of Maryland-College Park who was also involved in the study.

“The MPER is one of the virus’s weak points,” he said.

The discovery of this vaccine candidate is not enough for a vaccine that can go into production and dissemination but represents an important breakthrough because it has neutralizing characteristics against a broad range of HIV strains, a quality called heterologous neutralization.

“This study was the first to show that a vaccine can induce heterologous neutralizing antibodies from B cell lineages that have a degree of broadly neutralizing B cell antibodies for HIV,” Haynes said. ​“We may not yet have a working vaccine, but this study is definitely a valuable new proof of concept that vaccines can induce these unusual antibodies.”

Some of the antibodies that become broadly neutralizing all share a particular gene sequence, called VH7-4-1, which is favored through several different immunizations.

“These antibodies that contain this gene are enriched in terms of their neutralizing ability,” Ofek said.

In order to study the antibodies and virus, Ofek and the other researchers used SER-CAT at the APS. The crystallographic studies, which involved examining cryocooled crystals of the target protein with bound MPER-generated antibodies, was aided by the brilliance of APS X-ray beams that provided data and resulting structures of the highest quality. 

Rose noted that Argonne’s strengths in protein crystallography and structure determination made it the ideal place for the vaccine discovery.

“More than 50% of all protein structures from the United States that are deposited yearly in the Protein Data Bank come from the APS,” he said. 

With the ongoing upgrade to the APS, there is the potential for easier and more rapid characterization and structure determination, Rose said. ​“We’re getting to the point where we can do automated, no human required, crystallography at all hours of the day, greatly increasing our throughput,” he said.

“Argonne, with the APS Upgrade, is now one of the most modern facilities in the world for protein science,” Rose added.

A paper based on the study appeared in the journal Cell. This work was funded by a grant for the Consortia for HIV/AIDS Vaccine Development to Duke University from the Division of AIDS, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. 

About the Advanced Photon Source

The U. S. Department of Energy Office of Science’s Advanced Photon Source (APS) at Argonne National Laboratory is one of the world’s most productive X-ray light source facilities. The APS provides high-brightness X-ray beams to a diverse community of researchers in materials science, chemistry, condensed matter physics, the life and environmental sciences, and applied research. These X-rays are ideally suited for explorations of materials and biological structures; elemental distribution; chemical, magnetic, electronic states; and a wide range of technologically important engineering systems from batteries to fuel injector sprays, all of which are the foundations of our nation’s economic, technological, and physical well-being. Each year, more than 5,000 researchers use the APS to produce over 2,000 publications detailing impactful discoveries, and solve more vital biological protein structures than users of any other X-ray light source research facility. APS scientists and engineers innovate technology that is at the heart of advancing accelerator and light-source operations. This includes the insertion devices that produce extreme-brightness X-rays prized by researchers, lenses that focus the X-rays down to a few nanometers, instrumentation that maximizes the way the X-rays interact with samples being studied, and software that gathers and manages the massive quantity of data resulting from discovery research at the APS.

This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology by conducting leading-edge basic and applied research in virtually every scientific discipline. Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

The U.S. Department of Energy’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit https://​ener​gy​.gov/​s​c​ience.