Dense O-glycosylation of viral proteins has been widely described to provide “bulk” shielding from host immunity, and protect from antibody neutralization (Machiels et al. 2011; Kropff et al. 2012). Besides shielding select immunodominant epitopes (Machiels et al. 2011), highly O-glycosylated mucin-like domains, such as those found in Ebola and Marburg viruses, have been suggested to physically hinder the interaction between virus-infected cells and immune cells (Francica et al. 2010; Noyori et al. 2013). Conversely, the deletion of the Ebola virus mucin-like domain decreased the immune response in mice, although it did not have an effect on immunogenicity in vitro (Dowling et al. 2007). Finally, O-glycans not only shield, but in some cases can be presented as part of neo-epitopes when elongation of the glycans is prevented. As an example, several O-glycosylated immunodominant B-cell epitopes have been reported for HSV-2 and EBV, by probing O-glycopeptides with sera of infected patients, suggesting that the glycan moiety can be recognized by B-cells (Clo et al. 2012; D’Arrigo et al. 2013).