Two Academia Sinica teams have uncovered crucial details of how the vaccinia virus propagates, which could lead to the production of new vaccines against smallpox and related viruses, the Taipei City-based insititute said Aug. 27.
Although smallpox was eliminated worldwide following a U.N. campaign, vaccinia virus is considered to be safe for research purposes and researchers have focused on how vaccinia virus structure proteins work to improve future vaccine design.
The teams, led by Andrew H. J. Wang at the Institute of Biological Chemistry and Chang Wen at the Institute of Molecular Biology, uncovered the crystal structure of the vaccinia envelope A27 protein and showed the A27 protein trimer, a compound of three macromolecules, is the structural unit critical for vaccinia virus to leave cells and spread. The research was published in the Aug. 23 issue of scientific journal PLoS Pathogens.
Protein A27 also controls viral fusion suppressor complex formation, or the production of compounds that inhibit viral combination, the team found. Deciphering the viral membrane protein structure will aid in design of improved vaccines for the poxvirus family, which includes mouse pox, sheep pox and monkey pox, in the future, the institute said.
Vaccinia virus has more than 20 envelope proteins, including the A27 protein, which it shares with pox viruses such as variola and monkey pox, according to the research teams. The protein has multiple functions in the virus life cycle. When the virus enters a healthy cell, A27 mediates the attachment of vaccinia virus to the cell surface. A27 also attaches a viral fusion suppressor protein, A26, to mature virions. During virion morphogenesis, A27 mediates mature virus transport in infected cells.
Wang’s lab used X-ray crystallography to determine the structure of A27 protein, the institute said. Based on the crystal structure, Chang’s lab generated a series of mutant vaccinia viruses that interrupt the A27 protein-to-protein contact interface, resulting in attenuation of virus egress and virus spreading in cells.
Chang’s lab also demonstrated that A27 protein complex formation is crucial to its biological activity in vivo, and revealed how A27 regulates virus-induced membrane fusion through its ability to form complexes with A26 protein.
The researchers said that since A27 is a critical target of neutralizing antibodies against pathogenic poxvirus infection in humans, the findings provide a structural basis for the development of anti-pox drugs and vaccines. (SDH)
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