Breakthrough opens new ways to fight the deadly virus

Posted on April 10 in Review Cell Host & MicrobeThis major breakthrough has been made possible by the use of a molecular "opener" to expose portions of the virus envelope that may be targeted by antibodies.

"The characterization of the new form of the virus envelope reveals unique details about the vulnerability of HIV that could be useful in strategies to eradicate it," said Andrés Finzi, one of the leading authors from the study, researcher at CRCHUM. professor at the University of Montreal. "This certainly opens new avenues in the fight against this deadly virus."

When HIV infects the cells of the human immune system, it uses the tip of its envelope to attach to specific receptors on the cells, called CD4 and CCR5. The 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 the University of Pennsylvania to force the virus to open up and expose vulnerable parts of its envelope, allowing cells in the immune system to kill infected cells.

In an earlier study published in PNAS in 2015, researchers led by Finzi showed that exposure of these vulnerable parts of the envelope facilitates the removal of infected cells through a mechanism called antibody-dependent cellular cytotoxicity (ADCC).

How to map HIV vulnerabilities

Tufts researchers were able to visualize the previously unknown form of the virus envelope using a new technology – the single-molecule Förster resonance energy transfer, or smFRET – that allows researchers to see how Separate elements of the envelope move relative to each other. This provides a direct way to see that the HIV envelope is a dynamic machine with moving parts that allows it to take various forms in response to stimuli such as antibodies or small molecules.

"We hope that visualizing the shape of the virus envelope will contribute to the development of candidate vaccines that specifically exploit ADCC," said James Munro, lead author of the study and an adjunct professor of Molecular Biology and Microbiology at the Faculty of Medicine of Tufts University. of the pioneering team in the use of smFRET to better understand how the HIV-1 virus infects a human cell in real time. "In the vaccine trial in Thailand, so far, the only vaccine trial with a modest level of protection against HIV infection, the generation of antibodies with ADCC activity was a factor correlated with protection against the virus. "

The smFRET results were confirmed by cryo-electronic microscopy (cryo-EM), a technique adopted nearly 20 years ago by Isabelle Rouiller, principal author of the study and badociate professor at the University. from Melbourne. scientific community.

"It's fascinating to see how viruses protect themselves. Modern approaches such as single-particle cryo-EM now allow us to examine in detail the molecular mechanisms developed during evolution. Direct visualization of molecules on the surface of HIV will allow us to develop strategies for the disease. It's a dream come true! "said Rusty.

In 2017, nearly 37 million people were living with HIV. Every day, 5,000 new infections are reported to health authorities around the world.

This content only engages the responsibility of their authors and does not necessarily represent the official views of the National Institutes of Health or other funders.

The study was funded by the Canadian Institutes of Health Research, the National Institute of Health Research, the American Foundation for AIDS Research and the National Institute of Allergic and Infectious Diseases of the National Institutes of Health. 1K22AI116262). James Munro is also supported by the Gilead Sciences Research Institute HIV Research Program and the Campbell Foundation. Isabelle Rouiller is supported by the STEM-M – University of Melbourne Stimulus Fund and Andrés Finzi holds the Canada Research Chair in Retroviral Entry.