Hepatitis C virus compartmentalisation: unravelling the genetic complexity

Hedegaard, Ditte Christiane Emma Lindemann (2014). Hepatitis C virus compartmentalisation: unravelling the genetic complexity. University of Birmingham. Ph.D.

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Abstract

Hepatitis C virus (HCV) is a global health problem with over 150 million individuals infected worldwide. Many of these patients will develop end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma (HCC), and will require liver transplantation.

HCV exists as a heterogeneous population in infected individuals, however, the processes which maintain this genetic complexity are unknown. Recent observations suggest that HCV transmits between hepatocytes via a cell-to-cell route of infection, supporting a “demic” model of evolution where HCV diversity arises from independent evolution in small isolated hepatic populations.

To investigate the distribution of HCV within the liver we sampled eight segments of the liver explant from 22 HCV infected subjects undergoing liver transplant and measured viral RNA burden and sequence diversity. Comparable HCV RNA levels were observed across all 8 samples from a single liver, however, between patients we observed a 100-fold range in the hepatic viral load that was independent of hepatic expression of anti-viral and pro-viral interferon stimulated genes (ISGs). Sequence analysis of the viral envelope E1E2 region, obtained from PCR generated single molecules or ultra-deep sequencing approaches, showed minimal evidence of genetic compartmentalisation between hepatic sites or between the liver and plasma.

Modelling the HCV population structure in infected patients will have a major impact on our understanding of how HCV escapes host immune responses and anti-viral therapies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):