Herpes Simplex Virus Glycoprotein B Mutations Define Structural Sites in Domain I, the Membrane Proximal Region, and the Cytodomain That Regulate Entry
Qing Fan, Richard Longnecker, Sarah A. Connolly
Abstract
The nine human herpesviruses are ubiquitous and cause a range of diseases in humans. Glycoprotein B (gB) is an essential viral fusion protein that is conserved in all herpesviruses. During host cell entry, gB mediates virus-cell membrane fusion by undergoing a conformational change. Structural models for the prefusion and postfusion forms of gB exist, but the details of how the protein converts from one to the other are unclear. We previously introduced structure-based mutations into gB that inhibited virus entry and fusion. By passaging this entry-deficient virus over time, we selected second-site mutations that partially restore virus entry. The locations of these mutations suggest regulatory sites that contribute to fusion and gB refolding during entry. gB is a target of neutralizing antibodies, and defining how gB refolds during entry could provide a basis for the development of fusion inhibitors for future research or clinical use.