Can virus-based defective interfering particles (DIPS) be used to treat dengue infection?

Overview

Infection by dengue virus causes incapacitating and potentially dangerous acute disease in humans. Dengue is a mosquito-borne infectious disease with about 100 million serious clinical infections annually. Considerable effort in drug development is underway, but no effective drug therapy is available. A major difficulty for drug development is the rapid evolution of RNA viruses, like dengue virus, which presents a major challenge for controlling virus transmission and infection using conventional pharmaceuticals and vaccines.

This project is based on the observation that almost all viruses, and especially RNA viruses, produce copious amounts of defective viral RNA genomes (DVGs). Some of these DVGs, also called defective interfering (DI) RNA, are able to impede the growth of the wild type virus in the host. This project investigates and further develops new virus-derived antiviral-agents based on dengue virus and consists of virus-like particles that incorporate dengue-derived DI RNA. These are called defective interfering particles or DIPs. We can mass-produce DIPs using a novel in vitro system. We have created a single DIP that inhibits replication of all dengue virus strains tested in infected human cells. The goals of the project will:

1. Test DI RNA antiviral activity against dengue virus in a small animal model as a proof-of-principle that DIPs conveying antiviral DI RNA have therapeutic potential.
2. Test if dengue virus DI RNA exhibits antiviral activity against other Flaviviruses such as yellow fever, Zika and West Nile viruses. In addition, we will use a dengue virus-based DI RNA as a model to develop DI RNAs that are potent inhibitors for the aforementioned viruses.

Approaches/skills and techniques

Techniques used in this project include tissue culture, synthesis of synthetic RNA, transfection of cells with RNA or DNA, PCR and RT-qPCR, virus-like particle purification by various methods including colum chromatography, protein analysis by western bot and other methods, and virus plaque assays.

Outcomes

In summary, the project seeks to shift the paradigm of targeted, often ‘drug’-based, antiviral research by producing and evaluating a novel technology platform, DI RNA delivered by DIPs, that can be easily adapted for current and emerging viral pandemics such as for Zika and West Nile viruses and coronaviruses like SARS-CoV-2.

Required skills and experience

Some skills in tissue culture would be helpful. Experience in molecular biology techniques would be useful.

Keywords

• dengue
• infectious diseases
• mosquito-borne disease

Contact

QUT: Dr Francesca Frentiu

QIMRB: A/Prof David Harrich