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Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis.

Xuping Xie1, Yujiao Yang1,2, Antonio E Muruato3,4

  • 1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.

Mbio
|February 9, 2017
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Summary

Zika virus (ZIKV) stability is determined by its prM-E genes, not extra hydrogen bonds. Chimeric viruses of ZIKV and dengue virus (DENV) show potential as vaccines against both flaviviruses.

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Area of Science:

  • Virology
  • Structural Biology
  • Immunology

Background:

  • Zika virus (ZIKV) is uniquely associated with congenital diseases, unlike other flaviviruses.
  • Previous studies suggested ZIKV's higher thermostability, potentially linked to its E protein structure, may influence disease outcomes.
  • The role of specific structural features, like extended loops and hydrogen bonds in the ZIKV envelope (E) protein, in virion thermostability and infectivity was hypothesized.

Purpose of the Study:

  • To functionally analyze the structural basis of ZIKV's thermostability in complete virions.
  • To investigate the role of the prM-E genes and specific E protein structures in ZIKV virion stability and assembly.
  • To evaluate the potential of chimeric ZIKV-DENV viruses as vaccine candidates.

Main Methods:

  • Gene swapping of prM-E proteins between ZIKV and dengue virus serotype 2 (DENV-2) to create chimeric viruses.
  • Functional analysis of chimeric viruses and mutants with altered E protein structures (loop length, hydrogen bonds) in ZIKV assembly and thermostability.
  • Assessment of chimeric virus attenuation, immunogenicity, and protective efficacy in A129 mice (type I interferon receptor-deficient).

Main Results:

  • The prM-E genes were identified as the primary determinants of virion thermostability for ZIKV.
  • Shortening the E protein's extended loop was lethal for ZIKV assembly, while extra hydrogen bonds did not significantly contribute to thermostability.
  • Chimeric viruses (ZIKV with DENV-2 prM-E, and DENV-2 with ZIKV prM-E) were highly attenuated in mice, yet induced robust neutralizing antibody responses and provided cross-protection against ZIKV and DENV-2 challenge.

Conclusions:

  • ZIKV virion thermostability is primarily governed by its prM-E genes, with the extended E protein loop being crucial for assembly.
  • The extra hydrogen bond interaction observed in ZIKV's E protein does not enhance virion stability.
  • Chimeric ZIKV-DENV viruses are promising candidates for developing broadly protective flavivirus vaccines.