Defective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoes

PLoS Pathog. 2021 Feb 8;17(2):e1009110. doi: 10.1371/journal.ppat.1009110. eCollection 2021 Feb.

Abstract

Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aedes / virology*
  • Animals
  • Antiviral Agents / pharmacology*
  • Chikungunya Fever / immunology
  • Chikungunya Fever / transmission*
  • Chikungunya Fever / virology
  • Chikungunya virus / genetics*
  • Chikungunya virus / growth & development
  • Chikungunya virus / isolation & purification
  • Defective Viruses / genetics*
  • Genome, Viral*
  • Humans
  • Mosquito Vectors / virology
  • Virus Replication*

Substances

  • Antiviral Agents

Grant support

This work was funded by the DARPA INTERCEPT program managed by Dr. Jim Gimlett, Dr. Brad Ringeisen and Dr. Seth Cohen, and administered though DARPA Cooperative Agreement #HR0011-17-2-0023 to M.V. and M-C.S. (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 was also funded by the Laboratoire d'Excellence “Integrative Biology of Emerging Infectious Diseases” (grant ANR-10-LABX-62-IBEID) to M.V. and M-C.S., and the Equipe FRM grant #EQU201903007777 from the French Foundation for Medical Research to M.V. L.I.L. was funded by a doctoral fellowship from France’s defence procurement agency (DGA). None of the funders indicated above had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.