Particularly, the dendritic cell surface tetrameric lectin, DC-SIGN, and its closely related endothelial cell surface lectin, DC-SIGNR, (collectively abbreviated as DC-SIGN/R hereafter), play a key role in binding of the HIV and Ebola virus (EBOV) to augment viral entry and infection. After binding, viruses are internalised into host cells, mainly into endosomes and then subsequently trafficked to lysosomes following the natural endocytotic and trafficking pathways. During which, the bound lectinvirus complexes are exposed to a gradually acidified environment in such intracellular compartments, which plays a crucial role for the infectivity of viruses. The weakly acidic environment of early (pH ∼6) or late (pH ∼5) endosomes generally leads to the dissociation of the lectin-virus complexes, which is important for virus endosomal escape to retain infectivity. In case no dissociation happens in endosomes, the complexes may be trafficked to lysosomes (pH ∼4.6) for degradation, this often results in the loss of viral infectivity. Therefore, understanding the pH-dependent glycan binding and releasing properties of DC-SIGN/R is of great interest and importance to biology, although the resulting processes are still not fully understood.