Identification of the Structural Basis of Thermal Lability of a Virus Provides a Rationale for Improved Vaccines

• Published in: Structure (London) 2014-11, Vol.22 (11), p.1560-1570
• Main Authors: Rincón, Verónica, Rodríguez-Huete, Alicia, López-Argüello, Silvia, Ibarra-Molero, Beatriz, Sanchez-Ruiz, Jose M., Harmsen, Michiel M., Mateu, Mauricio G.
• Format: Article
• Language: English
• Subjects: Biology; Capsid Proteins - chemistry; charge-charge interactions; Charging; design; Determinants; empty capsids; Foot-and-mouth disease virus; Foot-and-Mouth Disease Virus - genetics; Foot-and-Mouth Disease Virus - physiology; guinea-pigs; insect cells; Models, Molecular; mouth-disease virus; Mutagenesis, Site-Directed; Nanostructure; particles; Phenotype; protein; Residues; RNA, Viral - genetics; stability; Static Electricity; Structure-Activity Relationship; surface; Temperature; Thermal dissociation; Transfection; Vaccines; Viral Vaccines - chemistry; Virion - chemistry; Virion - genetics; Virus Integration; Viruses
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2014.08.019

Virus stability and dynamics play critical roles during infection. Some viruses, including foot-and-mouth disease virus (FMDV), are surprisingly prone to thermal dissociation outside the cell. The structural bases and functional implications of this distinctive trait were essentially unknown. This study (1) uncovers the structural determinants of FMDV thermolability, (2) investigates the relationship between virus thermolability and infectivity, and (3) provides a structure-based rationale for engineering thermostable virus particles to develop improved vaccines and nanocontainers. The results reveal that negatively charged residues close to protein-protein interfaces exert electrostatic repulsions between capsid subunits and mediate the sensitivity of the virion to thermal dissociation, even at neutral pH. Based on these results, a series of fully infectious virions of increased thermostability were engineered by individually removing different carboxylates involved in intersubunit repulsions. The implications for virus biology and the design of thermostable vaccines are discussed. •Electrostatic repulsions mediate the low thermal resistance of an infectious virus•A structure-based rationale for viral vaccine thermostabilization is implemented•Electrostatic calculations may guide the engineering of thermostable virus particles•Increased virion thermostability does not involve a reduction in infectivity Rincón et al. show that thermolability of foot-and-mouth disease virus is mediated by electrostatic repulsion between negatively charged residues close to protein-protein interfaces. Fully infectious virions of increased thermostability, which are important for the development of thermostable vaccines, were obtained by mutating these charged residues.