If the human immunodeficiency virus (HIV) can be pictured as a sealed tin can, what would you see if you broke it open? An international team led by researchers at the University of Montreal Hospital Research Centre (CRCHUM), Tufts University, the University of Melbourne, and the University of Pennsylvania visualized for the first time how this “open can” adopts a shape that was unknown until now, providing a detailed image of the vulnerabilities of the virus.
Published in the journal Cell Host and Microbe, this major breakthrough was made possible through the use of a molecular “can opener” to expose parts of the virus envelope that can be targeted by antibodies.
“The characterization of the new shape of the envelope of the virus reveals unique details about the vulnerability of HIV that might be useful in strategies aimed at its eradication. It certainly opens new paths in the fight against this deadly virus,” says Andrés Finzi, one of the lead authors of the study, a researcher at the CRCHUM, and a professor at Université de Montréal.
When HIV infects cells of the human immune system, it attaches itself to specific receptors on these cells, CD4 and CCR5, using its envelope “spike.” Binding to the CD4 receptor triggers changes in the shape of the envelope that allow the virus to infect the host cell.
The new research describes the use of small-molecule CD4-mimetic compounds designed and synthesized at Penn’s Department of Chemistry to force the virus to open up and to expose vulnerable parts of its envelope, allowing the immune system cells to kill the infected cells. “This new research was made possible by compounds which were designed and synthesized here at Penn and is work that has been built upon by a number of collaborators from the above institutions,” says Amos B. Smith III.
In an earlier study published in PNAS in 2015, research led by Finzi showed that exposing the vulnerable parts of the envelope facilitates the elimination of infected cells by a mechanism known as antibody-dependent cellular cytotoxicity (ADCC).
Tufts University School of Medicine researchers were able to visualize the previously unknown shape of the virus envelope using a new technology: single-molecule Förster resonance energy transfer, or smFRET—that allows researchers to see how distinct elements of the envelope move with respect to one another. This provides a direct method for seeing that the HIV envelope is a dynamic machine with moving parts that allows it to adopt different shapes in response to different stimuli like antibodies or small molecules.
“We hope that visualizing the virus envelope’s shape will help in the development of vaccine candidates that specifically exploit ADCC. In the Thai vaccine trial (to date the only vaccine trial that showed a modest level of protection from HIV infection), generation of antibodies with ADCC activity was one factor correlated with protection from the virus,” says James Munro, a lead author of the study and assistant professor of molecular biology and microbiology at Tufts University School of Medicine. Munro was part of the team that pioneered the use of smFRET to better understand how the HIV-1 virus infects a human cell in real time.
The smFRET results were confirmed using cryo-electron microscopy (cryo-EM), a technique adopted by Isabelle Rouiller, a lead author of the study and a researcher at the University of Melbourne, that has recently gained recognition by the scientific community.
“It is fascinating how viruses protect themselves. Modern approaches such as single particle cryo-EM now allow us to look in detail at the molecular mechanisms developed through evolution. Directly visualizing the molecules at the surface of HIV will allow us to devise strategies to cure disease, a dream comes true!” says Rouiller.
In 2017, nearly 37 million people were infected with HIV worldwide. Every day, 5,000 new infections are reported to world health authorities.
Adapted from a news release provided by the Universite de Montreal, Tufts University School of Medicine, and the University of Melbourne.
This research was supported by the Canadian Institutes of Health Research, National Institute of Health Research, American Foundation for AIDS Research, National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Grant 1K22AI116262), and the National Institutes of Health (Grant P01 GM056550).
Amos B. Smith III is the Rhodes-Thompson Professor of Chemistry in the Department of Chemistry in the School of Arts and Sciences at the University of Pennsylvania.