Reverse genetics systems as tools for the development of novel therapies against filoviruses

Abstract

Filoviruses cause severe hemorrhagic fevers with case fatality rates of up to 90%, for which no antivirals are currently available. Their categorization as biosafety level 4 agents restricts work with infectious viruses to a few maximum containment laboratories worldwide, which constitutes a significant obstacle for the development of countermeasures. Reverse genetics facilitates the generation of recombinant filoviruses, including reporter-expressing viruses, which have been increasingly used for drug screening and development in recent years. Further, reverse-genetics based lifecycle modeling systems allow modeling of the filovirus lifecycle without the need for a maximum containment laboratory and have recently been optimized for use in high-throughput assays. The availability of these reverse genetics-based tools will significantly improve our ability to find novel antivirals against filoviruses.

Keywords::

• antiviral screening
• Ebola virus
• filoviruses
• marburg virus
• minigenome system
• recombinant virus
• reporter-expressing virus
• reverse genetics
• transcription and replication-competent particle system

Acknowledgements

The authors are very grateful to Allison Groseth (NIH/NIAID) for critical reading of the manuscript.

Financial & competing interests disclosure

This research was supported by the Intramural Research Program of the NIH, NIAID. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Reverse genetics systems encompass full-length clone systems, which allow the generation of recombinant viruses, and lifecycle modeling systems.

• Recombinant filoviruses expressing reporter genes can be used under biosafety level 4 conditions for rapid screening of antivirals, as well as for the confirmation of antiviral activity, and in some cases also the elucidation of the mechanism of action of these antivirals.

• Over the last years reporter-expressing filoviruses have been increasingly employed for antiviral screening using high-content imaging.

• Lifecycle modeling systems allow modeling of the lifecycle of filoviruses under biosafety level 2 conditions and can be used for antiviral screening purposes, as well as for the elucidation of mechanisms of action of antiviral drugs.

• These lifecycle modeling systems have only recently been optimized for high-throughput applications.

• The near future will see an increase in studies using reverse genetics-based tools for the development of antivirals.

Notes