Single Amino Acid Mutations Affect Zika Virus Replication In Vitro and Virulence In Vivo

Collette, Nicole M.; Lao, Victoria I.; Weilhammer, Dina R.; Zingg, Barbara; Cohen, Shoshana D.; Hwang, Mona; Coffey, Lark L.; Grady, Sarah L.; Zemla, Adam T.; Borucki, Monica K.

doi:10.3390/v12111295

Title: Single Amino Acid Mutations Affect Zika Virus Replication In Vitro and Virulence In Vivo

Journal Article · Thu Nov 12 00:00:00 EST 2020 · Viruses

DOI:https://doi.org/10.3390/v12111295· OSTI ID:1765791

; Lao, Victoria I.; Weilhammer, Dina R.; Zingg, Barbara;

; Hwang, Mona;

; Grady, Sarah L.; Zemla, Adam T.;

The 2014–2016 Zika virus (ZIKV) epidemic in the Americas resulted in large deposits of next-generation sequencing data from clinical samples. This resource was mined to identify emerging mutations and trends in mutations as the outbreak progressed over time. Information on transmission dynamics, prevalence, and persistence of intra-host mutants, and the position of a mutation on a protein were then used to prioritize 544 reported mutations based on their ability to impact ZIKV phenotype. Using this criteria, six mutants (representing naturally occurring mutations) were generated as synthetic infectious clones using a 2015 Puerto Rican epidemic strain PRVABC59 as the parental backbone. The phenotypes of these naturally occurring variants were examined using both cell culture and murine model systems. Mutants had distinct phenotypes, including changes in replication rate, embryo death, and decreased head size. In particular, a NS2B mutant previously detected during in vivo studies in rhesus macaques was found to cause lethal infections in adult mice, abortions in pregnant females, and increased viral genome copies in both brain tissue and blood of female mice. Additionally, mutants with changes in the region of NS3 that interfaces with NS5 during replication displayed reduced replication in the blood of adult mice. This analytical pathway, integrating both bioinformatic and wet lab experiments, provides a foundation for understanding how naturally occurring single mutations affect disease outcome and can be used to predict the of severity of future ZIKV outbreaks.

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Research Organization:: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); Univ. of California, Davis

Grant/Contract Number:: AC52-07NA27344; P51OD011107

OSTI ID:: 1765791

Report Number(s):: LLNL-JRNL-813141; 1020884

Journal Information:: Viruses, Vol. 12, Issue 11; ISSN 1999-4915

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Zika virus
mutation
variant
A129 mouse model
microcephaly
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quasispecies

Title: Single Amino Acid Mutations Affect Zika Virus Replication In Vitro and Virulence In Vivo

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