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Co-localisation of hepatitis C virus drug-resistant mutations and immune-driven adaptations: Relevance to therapy outcome

Gaudieri, S., Rauch, A., James, I., Pfafferott, K., Baker, R., Cheng, W., McCaughan, G., Shackel, N., Jeffrey, G., Mollinson, L., Mallal, S., Furrer, H., Günthard, H., Hirschel, B., Klenerman, P., Nolan, D., John, M. and Lucas, M. (2009) Co-localisation of hepatitis C virus drug-resistant mutations and immune-driven adaptations: Relevance to therapy outcome. In: 19th Annual Combined Biological Sciences Meeting 2009, 28 August 2009, Perth, Western Australia.

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Recent advances in molecular virology have led to the development of novel small anti-HCV drugs that target specific viral proteins integral to the HCV life cycle. Preliminary studies using these agents have revealed a number of drug-resistance mutations within the target HCV proteins. We, and others, have previously demonstrated the influence of the host’s immune response on viral diversity at both the individual and population level and identified sites within the HCV genome that are under immune pressure. In this study, the frequency of pre-existing drug resistance mutations within a drug-naïve population is determined and the potential for drug and immune selective pressures to intersect at sites along the HCV genome is explored. We obtained complete or partial sequence of the NS3/4A protease and NS5B polymerase from plasma samples from 264 genotype 1 and 147 genotype 3 HCV-infected individuals. High-resolution Human Leucocyte Antigen (HLA) typing was performed on DNA samples from individuals in this cohort. The baseline occurrence of drug resistance mutations can be observed at low frequencies in the drug naïve population, explaining why many observed drug resistance mutations occur rapidly after introduction of the drug. Furthermore, there are overlaps in areas of NS3/4A protease and NS5B polymerase that are likely to be under immune pressure and therapy selection. However, this overlap between the selective pressures is likely to be genotype specific as the differences at the amino acid level between the genotypes produces limited overlap in the sites along the viral genome that are under immune pressure. Drug and immune selection pressures may act synergistically or as opposing forces in HCV proteins that are targeted by the new anti-HCV drugs. Accordingly, an individual’s HCV immune escape and drug resistance profile are likely to be critical influences on the outcome with specific antiviral treatments.

Publication Type: Conference Item
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
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