Abstract
The main antivirals employed to combat seasonal and pandemic influenza are oseltamivir and zanamivir which act by inhibiting the virus-encoded neuraminidase. These have to be deployed close to the time of infection and antiviral resistance to the more widely used oseltamivir has arisen relatively rapidly. Defective interfering (DI) influenza virus is a natural antiviral that works in a different way to oseltamivir and zanamivir, and a cloned version (segment 1 244 DI RNA in a cloned A/PR/8/34 virus; 244/PR8) has proved effective in preclinical studies in mice. The active principle is the DI RNA, and this is thought to interact with all influenza A viruses by inhibiting RNA virus synthesis and packaging of the cognate virion RNA into nascent DI virus particles. We have compared the ability of DI virus and oseltamivir to protect ferrets from intranasal 2009 pandemic influenza virus A/California/04/09 (A/Cal, H1N1). Ferrets were treated with a single 2μg intranasal dose of 244 DI RNA delivered as 244/PR8 virus, or a total of 25mg/kg body weight of oseltamivir given as 10 oral doses over 5days. Both DI virus and oseltamivir reduced day 2 infectivity and the influx of cells into nasal fluids, and permitted the development of adaptive immunity. However DI virus, but not oseltamivir, significantly reduced weight loss, facilitated better weight gain, reduced respiratory disease, and reduced infectivity on days 4 and 6. 244 DI RNA was amplified by A/Cal by >25,000-fold, consistent with the amelioration of clinical disease. Treatment with DI virus did not delay clearance or cause persistence of infectious virus or DI RNA. Thus in this system DI virus was overall more effective than oseltamivir in combatting pandemic A/California/04/09.
Highlights
Defective interfering (DI) viruses are natural mutants that arise spontaneously, occur widely, and have a genome that has undergone at least one major deletion
Data presented here show that a single intranasal dose of 2 lg of DI RNA is overall more effective than 10 doses of 2.5 mg/kg bodyweight administered twice daily over five days (25 mg/kg in total) of oseltamivir at ameliorating the effects of pandemic influenza virus A/California/04/09 (H1N1)
The haemagglutinin (HA) protein of the original 244/PR8 virus had a preference for cell receptors comprising a2,3-linked sialyl receptor sequences, so we reconstructed 244 DI virus with the HA protein of a PR8 virus that binds to both a2,6- and a2,3-linked sialyl receptors (Meng et al, 2010), so that DI RNA would be delivered to cells bearing both types of receptor, and protect against infectious viruses which recognise either type of receptor as described previously (Meng et al, 2010)
Summary
Defective interfering (DI) viruses are natural mutants that arise spontaneously, occur widely, and have a genome that has undergone at least one major deletion. We solved this problem using reverse genetics to make cloned DI viruses that contain one major species of DI RNA (Dimmock et al, 2008; Duhaut and Dimmock, 1998, 2000, 2002, 2003) One such influenza virus, containing the 244 DI RNA, derived from segment 1, strongly protected mice against disease caused by several different influenza A virus subtypes when inoculated intranasally (Dimmock et al, 2008). Data presented here show that a single intranasal dose of 2 lg of DI RNA is overall more effective than 10 doses of 2.5 mg/kg bodyweight administered twice daily over five days (25 mg/kg in total) of oseltamivir at ameliorating the effects of pandemic influenza virus A/California/04/09 (H1N1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
