Mapping the glycan shields of enveloped viruses

Glycosylation is a ubiquitous post-translational modification responsible for a multitude of crucial biological roles. As obligate parasites, viruses exploit host-cell machinery to glycosylate their own proteins during replication. Viral envelope proteins form a myriad of human pathogens including HIV-1, influenza virus, Lassa virus, coronaviruses, Zika virus, dengue virus, and Ebola virus have evolved to be glycosylated to varying degrees. These host cell derived glycans facilitate diverse structural and functional roles during the viral life-cycle ranging from aiding glycoprotein folding to enhancement of immune cell infection. As the primary focus of the humoral immune response, vaccine development efforts often concentrate on the viral glycoproteins that protrude from the virion envelope. This thesis primarily focuses on immune evasion of viruses by molecular mimicry and glycan shielding. The work presented here reveals how viral glycan shields from evolutionarily distinct pathogens share conserved features, namely clusters of underprocessed oligomannose-type glycans. Furthermore, this thesis explores how an anti-HIV-1 antibody, 2G12, that targets oligomannose-type glycans cross-reacts and neutralises more recent influenza strains, as they have evolved to accrete N-linked glycosylation sites on their respective hemagglutinins, which result in the formation of oligomannose clusters. These findings provide a potential avenue for the development of a broad class of antivirals, that can target conserved features of viral glycosylation. Comparisons of several viral glycan shields are also carried out which probes the rules governing glycan processing and the disparate efficacies of them. Given the prominence of N-linked glycosylation on viral glycoprotein surfaces, it is suggested that the compositional and structural data presented here can aid vaccine development and therapeutic efforts to combat these diseases.