Could sustained immune pressure on viral transmissibility eventually lead to the natural selection of virulence-enhancing changes in viral glycosylation?

I have previously expressed my amazement at the remarkable resilience of complex biological systems, such as the mammalian immune system, in mitigating and/or postponing the severe consequences of C-19 vaccine-induced viral immune escape on human health (https://www.voiceforscienceandsolidarity.org/scientific-blog/to-whom-it-may-concern). This resilience seems particularly applicable to viral immune escape mechanisms that threaten the survival of the host species. I have proposed that mutations in the glycosylation pattern of SARSCoV-2 could eventually drive viral evolution toward enhanced virulence, potentially resulting in rapid death (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-onevolution-c-19-pandemic). It is, therefore, reasonable to investigate whether evolutionary changes in the virus’s glycosylation profile could also contribute to attenuating viral virulence and/or delaying an explosion in mortality rates in highly C-19 vaccinated populations.

Based on the literature on viral glycosylation, as cited in one of my previous contributions on this topic (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-onevolution-c-19-pandemic), it seems highly likely that changes in viral glycosylation can lead to increased viral virulence. In the following discussion, and as an addition to a previous contribution, I explain why such changes could take longer to be selected under immune pressure compared to amino acid changes that directly enhance viral infectivity.

Glycosylation refers to the attachment of sugar molecules (glycans) to proteins or lipids. Glycans can either be N-linked or O-linked[1]. In viruses, glycosylation often occurs on surface proteins, such as the spike protein of coronaviruses or the hemagglutinin of influenza viruses. Glycans can shield critical viral epitopes and thereby mask these epitopes from antibody recognition, allowing the virus to evade immune detection and neutralization. This evasion can lead to higher virulence when glycosylation promotes viral infection or replication in an immunologically naïve population, or when it facilitates the transinfection of the virus to target tissues in immunologically experienced populations that remain susceptible to breakthrough infections. This is plausible, as glycosylation is known to modulate receptor binding affinity and specificity, potentially modifying the binding of antibodies to cell surface-expressed binding sites and altering the susceptibility of certain tissue cells.

While amino acid mutations in surface proteins responsible for viral infectivity can readily increase viral infectiousness and transmissibility (e.g., by preventing neutralizing antibodies from binding to the receptor-binding site on the ‘infectious’ viral protein) and confer an immediate fitness benefit, the selection of glycosylation changes may occur more slowly. This is because glycosylation involves both the protein sequence and the host's glycosylation machinery, adding complexity to the selection dynamics and how changes manifest. Since glycosylation changes can compromise viral fitness by reducing the efficiency of host cell entry or decreasing viral replication rates (e.g., due to alteration of protein folding, structural stability, or function), the natural selection of ‘beneficial’ immune escape mutations in the virus’s glycosylation pattern of surface proteins might require a distinct and sustained immune selection pressure, targeted at different viral epitopes that are not involved in mediating intrinsic viral infectiousness. This is because viral glycosylation patterns are often a balance between immune evasion and maintaining efficient host cell entry and replication. 

In summary, it is reasonable to state that, compared to direct amino acid changes, the evolutionary dynamics of viral glycosylation reflect a more intricate and context-dependent process that shapes viral adaptation under immune pressure, affecting their ability to persist and spread in host populations. Variants of SARS-CoV-2 are just one example of viruses that have exhibited mutations affecting their glycosylation (specifically, of the spike protein) when placed under sustained immune pressure[2] . The emergence of new immune escape variants endowed with beneficial glycosylation changes therefore likely requires selection over longer evolutionary periods.

Unfortunately, despite numerous precedents (e.g., Influenza virus, HIV-1, Human Rhinovirus, and Hepatitis C virus) and extensive documentation in virology textbooks, the significance of glycosylation mutations in SARS-CoV-2 and their potential impact on the outcome of the pandemic when selected under strong and sustained immune pressure is poorly understood and certainly underestimated.

References

1. N-linked Glycosylation: The glycan/ sugar is attached to the nitrogen atom (N) of the side chain of the amino acid asparagine (Asn). O-linked Glycosylation: The glycan/ sugar is attached to the oxygen atom (O) of the hydroxyl group of the side chains of the amino acids serine (Ser) or threonine (Thr)
2. For example, the emergence of variants like Delta and Omicron involved changes in the glycosylation pattern of the spike protein, contributing to altered immune responses and vaccine effectiveness