Structure of the Lassa virus glycan shield provides a model for immunological resistance

Significance Lassa virus is a highly pathogenic arenavirus that causes severe hemorrhagic fever in humans. Currently, there are no efficacious vaccines or treatments available to combat this pathogen. An important component of any vaccine candidate against Lassa virus will likely include the highly glycosylated glycoprotein complex presented on the virion surface. Here, we determine the composition of the Lassa virus glycome, revealing that the virus presents an abundance of glycans that are not biosynthetically processed to full maturity. Such underprocessed glycans form spatially distinct clusters, which shield the proteinous surface of the Lassa virus glycoprotein spike from the humoral immune response. These data are integral for the development of humoral-based vaccines that mimic the mature Lassa virion.
Lassa virus is an Old World arenavirus endemic to West Africa that causes severe hemorrhagic fever. Vaccine development has focused on the envelope glycoprotein complex (GPC) that extends from the virion envelope. The often inadequate antibody immune response elicited by both vaccine and natural infection has been, in part, attributed to the abundance of N-linked glycosylation on the GPC. Here, using a virus-like−particle system that presents Lassa virus GPC in a native-like context, we determine the composite population of each of the N-linked glycosylation sites presented on the trimeric GPC spike. Our analysis reveals the presence of underprocessed oligomannose-type glycans, which form punctuated clusters that obscure the proteinous surface of both the GP1 attachment and GP2 fusion glycoprotein subunits of the Lassa virus GPC. These oligomannose clusters are seemingly derived as a result of sterically reduced accessibility to glycan processing enzymes, and limited amino acid diversification around these sites supports their role protecting against the humoral immune response. Combined, our data provide a structure-based blueprint for understanding how glycans render the glycoprotein spikes of Lassa virus and other Old World arenaviruses immunologically resistant targets.