Conclusions
Enveloped viruses have long been known to hijack the host cell’s glycosylation machinery for glycosylation of viral proteins. The development and advancement of mass spectrometry techniques have paid a tremendous contribution to the characterization of precise location and structure of glycans decorating the viral envelope proteins, and revealed substantial heterogeneity of glycan structures and site occupancy. Moreover, glycan density, as well as N- to O-glycan ratio, varies greatly among different classes of viruses, with some being highly glycosylated, and others having only a few glycan chains. Accumulating site-directed mutagenesis data suggests that individual glycosites play diverse important roles in virus biology. Moreover, glycans heavily contribute to the overall structure of the glycoprotein, epitope accessibility, and, in some cases, directly affect immune recognition. While there are some examples where carbohydrate moieties directly participate in interactions, in many cases disrupted biological functions are results of impaired protein structure, localization or function. Failure to develop universal vaccines for multiple viruses such as HIV-1, HCV and HSV suggest that comprehensive knowledge of structure and immunogenicity of viral envelope proteins in relevant biological systems is needed to achieve desired immune responses. While the location and function of N-linked glycans have been very well characterized for many viruses, discovery of O-glycosites has been neglected due to the nature of O-glycan synthesis and analytical difficulties. We have developed techniques to globally address site-specific O-glycosylation of enveloped viruses and revealed unprecedented magnitude of O-glycosylation in herpesviruses. We argue that the contribution of O-glycans needs to be addressed for vaccine development in order to have a complete picture of post-translational modifications affecting the protein function and immunogenicity. It is hoped that the data summarized in this review will ignite more interest in viral O-glycosylation, and give rise to focused studies leading to a better understanding of virus biology and improved means to prevent and combat the associated infections.