Exploring the complexity of RNA virus infections using viral genomics

RNA viruses such as influenza, dengue, SARS, Ebola and yellow fever are a formidable threat to human health and global economy. They have small genomes, but due to the lack of proof-reading during RNA-to-RNA replication, these genomes harbour many mutations. Thus, in a single infected host, many different genomic variants exist. Until recently, it was not possible to sequence these within-host variants reliably due to technical limitations of sequencing platforms. Instead, most analysis were restricted to a representative “consensus” viral sequence per host, which is an oversimplification of the true diversity of these infections. While consensus level genome analyses have helped in understanding disease pathogenesis, designing better treatments or vaccines, contact tracing and predicting infection outcomes, using within-hostvariants in analyses could potentially achieve more. The work presented here describes the value of viral genomics in understanding the complexity of RNA virus infections and introduces cutting-edge technological advances we have made in identifying within-host viral variants in an infected host. This work used hepatitis C virus (a chronic infection) as a model and the optimised methods were subsequently adapted to study dengue virus (an acute infection). Chronic and acute RNA virus infections each pose unique challenges in viral genomics analyses and overcoming these challenges for both types of viruses ensures that these methods can be applied to study many other RNA viruses.