Structural overview of lyssavirus glycoproteins, antibodies, and receptors

Rabies virus is the most lethal virus ever discovered and remains a global health threat despite vaccines and post-exposure treatment. In addition to rabies, there are also 17 other lyssaviruses, several of which have already crossed species barriers to infect humans and cause the same clinical disease as the rabies virus. While effective in preventing rabies infection, current rabies vaccines do not provide long-lasting protection or elicit antibodies that are broadly protective against both rabies and related lyssaviruses. Efforts to improve rabies vaccines to elicit a uniform, longer-lasting, and more broadly neutralizing antibody response would benefit from structure-guided design, where high-resolution protein structures are used to engineer vaccine antigens. In the last 6 years, the first high-resolution structures of lyssavirus glycoproteins have become available, giving new insights into how these viruses interact with host antibodies and receptors, and making structure-guided antigen design feasible. This review encompasses recent findings in lyssavirus glycoprotein structure, interactions with neutralizing antibodies, and interactions with potential cellular receptors, with an emphasis on the rabies virus.