Vaccine researchers often have difficulty developing vaccines for viruses with slippery glycans. Many viruses such as HIV possess slippery glycans that grip onto and shield the protein surfaces of the virus from antibodies. These glycans form on the surface of peplomers, the spike proteins that cover viruses such as those present on HIV and SARS-CoV-2. Scientists from Scripps Research and Los Alamos National Laboratory have developed a technique to map out dense groups of glycans in great detail. These maps can give researchers a better idea of why some areas on the virus react to the antibodies while others do not. Finding the most vulnerable and accessible sites on these viruses can help researchers develop more efficient vaccines.
Antibodies work by identifying pathogens in the body and binding to the antigens present on the protein surface of a virus. Glycan shields form on the spike protein surface of viruses such as HIV, preventing adaptive recognition of key epitopes and binding of antibodies to the viruses. The abundance of glycan molecules in cells necessitates readily available shields which hinders an immune response. Sustainment of adaptive immune recognition has become a focal point for vaccine researchers.
The difficulty of capturing images of glycan shields is due to the internal motions within glycan molecules that hinder immune responses. To remedy this, the team of researchers combined cryo-electron microscopy (cryo-EM) with computer modeling and site-specific mass spectrometry. Like an augmented CT scan, cryo-EM takes hundreds of thousands of snapshots to create an image of a blur of glycan molecules. In conjunction with site-specific mass spectrometry, which identifies molecules, and computer modeling, researchers have been able to generate comprehensive maps of vulnerable sites on the spike surface of HIV. The team observed the nature of glycans to clump together instead of roam the viral surface individually. The lead author of this study, Zachary Berndsen, says, "There are chunks of glycans that seem to move and interact together. In between these glycan microdomains is where antibodies apparently have the opportunity to bind." The team also observed that the HIV glycan shield also functions to maintain the virus’ shape and stability, which is important for infection.
However, there are some restrictions on the team’s trials. For example, experimental vaccines rely on synthetic spike proteins. For HIV and possibly many other viruses, the glycan shield can vary depending on the type of cell that is used to produce it. While the virus in humans uses the body’s immune system to replicate viral proteins, other mammalian cells are used to produce these proteins in the vaccines. Despite these restrictions, the imaging techniques developed in this study are applicable to the design of vaccines for glycan-shielded viruses, including coronaviruses.
Linda G Baum, Brian A Cobb, The direct and indirect effects of glycans on immune function,
Glycobiology, Volume 27, Issue 7, July 2017, Pages 619–624
Scripps Research Institute. "New imaging method reveals HIV's sugary shield in unprecedented
detail." ScienceDaily. ScienceDaily, 23 October 2020.