Intra- And inter-cellular modeling of dynamic interaction between Zika virus and its naturally occurring defective viral genomes

Vadim Sharov, Veronica V. Rezelj, Vladimir V. Galatenko, Avi Titievsky, Julia Panov, Konstantin Chumakov, Raul Andino, Marco Vignuzzi, Leonid Brodsky

Research output: Contribution to journalArticlepeer-review

Abstract

Here, we examine in silico the infection dynamics and interactions of two Zika virus (ZIKV) genomes: one is the full-length ZIKV genome (wild type [WT]), and the other is one of the naturally occurring defective viral genomes (DVGs), which can replicate in the presence of the WT genome, appears under high-MOI (multiplicity of infection) passaging conditions, and carries a deletion encompassing part of the structural and NS1 protein-coding region. Ordinary differential equations (ODEs) were used to simulate the infection of cells by virus particles and the intracellular replication of the WT and DVG genomes that produce these particles. For each virus passage in Vero and C6/36 cell cultures, the rates of the simulated processes were fitted to two types of observations: virus titer data and the assembled haplotypes of the replicate passage samples. We studied the consistency of the model with the experimental data across all passages of infection in each cell type separately as well as the sensitivity of the model's parameters. We also determined which simulated processes of virus evolution are the most important for the adaptation of the WT and DVG interplay in these two disparate cell culture environments. Our results demonstrate that in the majority of passages, the rates of DVG production are higher inC6/36 cells than in Vero cells, which might result in tolerance and therefore drive the persistence of the mosquito vector in the context of ZIKV infection. Additionally, the model simulations showed a slower accumulation of infected cells under higher activation of the DVG-associated processes, which indicates a potential role of DVGs in virus attenuation.

Original languageEnglish
Article numbere00977-21
JournalJournal of Virology
Volume95
Issue number22
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding Information:
This work was funded by the DARPA Intercept program managed by Seth Cohen and administered through DARPA cooperative agreement no. HR0011-17-2-0023 and through contract no. HR0011-17-2-0027 (the content of the information does not necessarily reflect the position or the policy of the U.S. government, and no official endorsement should be inferred). This work also received funding from the Laszlo N. Tauber Family Foundation, the Fondation de Recherche Médicale (FRM EQU201903007777), and Agence Nationale de Recherche Laboratoire d’Excellence grant ANR-10-LABX-62-IBEID.

Funding Information:
We thank Stepan Nersisyan, Alexei Galatenko, and Vladimir Staroverov (Tauber Bioinformatics Research Center, University of Haifa, Israel, and Moscow State University, Moscow, Russia) for participation in establishing the ODE computational pipeline, valuable comments, and discussions. This work was funded by the DARPA Intercept program managed by Seth Cohen and administered through DARPA cooperative agreement no. HR0011-17-2-0023 and through contract no. HR0011-17-2-0027 (the content of the information does not necessarily reflect the position or the policy of the U.S. government, and no official endorsement should be inferred). This work also received funding from the Laszlo N. Tauber Family Foundation, the Fondation de Recherche M?dicale (FRM EQU201903007777), and Agence Nationale de Recherche Laboratoire d'Excellence grant ANR-10-LABX-62-IBEID.

Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.

Keywords

  • Defective virus genomes
  • Mathematical modeling
  • Zika virus

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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