|dc.contributor.author||Cunningham, Morven Elizabeth||
|dc.identifier.citation||Cunningham, M. 2016. Developing new models to predict treatment outcome in patients with chronic hepatitis C infection. Queen Mary University of London||en_US
|dc.description.abstract||Chronic infection with hepatitis C virus (HCV) is a significant global health
problem, with approximately 170 million individuals infected worldwide.
Treatment is rapidly evolving to combinations of highly potent direct-acting
antiviral drugs, although optimal combinations for individual patient groups are
not yet clear. Treatment failure still occurs, and relapse may occur in as many as
10% of treated individuals.
Whilst HCV replicates primarily in the liver, HCV RNA has been identified in
extrahepatic sites, including monocytes, although extrahepatic replication is
controversial. Our group recently developed a novel assay to study replication of
patient-derived HCV by fusion of patient monocytes with cultured hepatoma cells.
In this study, we extended the utility of this fusion model, by using cell culture
monocytes to ‘capture’ HCV from patient serum prior to fusion with hepatoma
cells. We studied whether this ‘capture-fusion’ model could be used to screen
individual patient drug response and the mechanisms permitting viral replication
in the hybrid cells.
Using the capture-fusion assay, patient-derived HCV of all viral genotypes
replicated to levels detectable by a sensitive PCR assay and could be inhibited
by antiviral drugs in a genotype-specific manner. Isolates with genotypic and
phenotypic drug resistance could be identified, and, in a blinded study, drug
sensitivity in the assay correlated with clinical treatment response. Relapse after
interferon and ribavirin treatment was associated with poor pre-treatment ribavirin
sensitivity and also with viable HCV in patient-derived monocytes at the end of
therapy. Uptake of HCV into monocytes appeared independent of classical HCV
entry receptors, and our work implicated CD64 in HCV monocyte entry. Cell
fusion appeared to permit transfer of HCV RNA to hepatocytes without triggering
an intracellular antiviral innate immune response.
Our data suggest that this novel ‘capture-fusion’ model represents a promising
new technique which may help identify appropriate treatment strategies for
patients with chronic HCV infection.||
|dc.description.sponsorship||Doctoral Research Fellowship from the National Institute for Healthcare Research (grant number DRF-2010-3-29).||en_US
|dc.publisher||Queen Mary University of London||en_US
|dc.title||Developing new models to predict treatment outcome in patients with chronic hepatitis C infection||en_US
|dc.rights.holder||The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author||