A classical lay summary by Srirupa Chakraborty, from Northeastern University.
The human immune system is generally adept at detecting and combating foreign invaders. However, enveloped viruses such as HIV, influenza, SARS-CoV-2, and Ebola among others, have evolved a clever strategy to evade it. The proteins expressed on the surfaces of these viruses are cloaked in a protective layer of complex sugars called glycans. This “glycan shield” acts as camouflage, literally, a sugar coating, for hiding the virus’s more vulnerable protein regions from the host’s immune system[1]. Understanding how this shield works—and finding its weak points—is a major focus of biophysical research, with the goal of designing better vaccines and therapies.
Glycans are complex branched polymers of sugar molecules covalently attached to proteins as post-translational modifications. Viruses, including HIV and influenza, decorate their surface proteins with these glycans to hide critical areas that antibodies would normally recognize to block an infection. This strategy helps the virus to persist longer inside the infected host organism and evade immune detection. However, some of these glycans can also become potential targets for the immune system, leading to a dual role of both protection and vulnerability. For example, the antibody 2G12 has been shown to bind to clusters of such glycans on HIV, preventing the virus from infecting cells[2]. Researchers have employed powerful techniques like cryo-electron microscopy (cryoEM) and mass spectrometry to map these glycan shields on the surface of viruses[3]. These methods allow scientists to study where the glycans are located and how they interact with antibodies. However, the glycan shield is not static – the glycans dynamically change conformations. They can also vary in size, shape, and density, and their arrangement can change over time as the virus evolves. This is where computational modeling comes in.
Computational approaches, such as molecular dynamics simulations, and network analysis help researchers simulate the movement and arrangement of glycans on the viral surface. These models can predict how glycans interact with proteins and even suggest potential weak spots where antibodies might bind. By modeling the structure and dynamics of the glycan shield, scientists can identify vulnerabilities that could be targeted by vaccines or antiviral drugs. The study of glycan shielding is opening new doors for understanding viral immunity and developing therapies. By mapping and modeling the structure and dynamics of these shields, scientists hope to design more effective treatments and vaccines for diseases caused by these devastating viruses.
1. Miller, N.L., et al., Glycans in Virus-Host Interactions: A Structural Perspective. Front Mol Biosci, 2021. 8: p. 666756.
2. Scanlan, C.N., et al., The broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2G12 recognizes a cluster of alpha1-->2 mannose residues on the outer face of gp120. J Virol, 2002. 76(14): p. 7306-21.
3. Watanabe, Y., et al., Exploitation of glycosylation in enveloped virus pathobiology. Biochim Biophys Acta Gen Subj, 2019. 1863(10): p. 1480-1497.