Abstract
Infection by hepatitis C virus (HCV) leads to one of two outcomes; either the infection resolves within approximately 6 months or the virus can persist indefinitely. Host genetics are known to affect the likelihood of clearance or persistence. By contrast, the importance of the virus genotype in determining infection outcome is unknown, as quantifying this effect traditionally requires well-characterized transmission networks, which are rare. Extending phylogenetic approaches previously developed to estimate the virus control over set-point viral load in HIV-1 infections, we simulate inheritance of a binary trait along a phylogenetic tree, use this data to quantify how infection outcomes cluster and ascertain the effect of virus genotype on these. We apply our method to the Hepatitis C Incidence and Transmission Study in prisons (HITS-p) data set from Australia, as this cohort prospectively identified incident cases including viraemic subjects who ultimately clear the virus, thus providing us with a unique collection of sequences from clearing infections. We detect significant correlations between infection outcome and virus distance in the phylogeny for viruses of Genotype 1, with estimates lying at around 67%. No statistically significant estimates were obtained for viruses of Genotype 3a.
Highlights
The hepatitis C virus (HCV; family Flaviviridae, genus Hepacivirus) is estimated to infect around 170 million people worldwide, and is a major cause of chronic liver disease (Simmonds 2004)
Correlation between virus genomes and infection outcome for all genome sequences Genetic data obtained from the HITS-p cohort mostly resolved itself into one of the two clades, HCV genotypes 1, and subtype 3a (Fig. 1)
The high level of virus control found for randomized tips likely reflects that, the log-likelihood of the switching rates decreases with increased virus control, the likelihood surface can be flat for a broad range of control values
Summary
The hepatitis C virus (HCV; family Flaviviridae, genus Hepacivirus) is estimated to infect around 170 million people worldwide, and is a major cause of chronic liver disease (Simmonds 2004). Due to the ensuing health burden caused by HCV, there is a considerable research focus on understanding how the host and the virus genetics shape the infection outcome (Ploss and Dubuisson 2012). There is a vast array of new therapies being developed that target both host (e.g. cyclophilin inhibitors, microRNA antagomirs (Janssen et al 2013)) and viral phenotypes (direct-acting antiviral agents targeting the HCV protease and polymerase; Ploss and Dubuisson 2012). Genetic polymorphisms in the promoter region of the host IL28B gene that correlate with an increased probability of HCV clearance have been detected (Ge et al 2009; Thomas et al 2009; Rauch et al 2010). It is clear that certain regions of the viral polyprotein are targeted by the host immune responses and are involved in clearance. There are multiple epitopes within the nonstructural (NS) region of the genome that are targeted by cellular immune response (CD8 cytotoxic T cells), giving rise to virus escape variants
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