Owen, Rachel Elizabeth; (2003) Immunomodulatory effects of the hepatitis C virus (HCV) core protein. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hepatitis C virus establishes a persistent infection in approximately 80% of infected individuals. It is unclear why the immune system is frequently unable to mediate a response capable of controlling HCV replication. Dendritic cells (DCs) may be an extrahepatic site of viral replication and it is hypothesised that expression of the core protein within DCs may impair their functions resulting in inadequate immune responses. To investigate potential immunomodulatory effects of the core protein on DCs, replication-deficient adenoviral vectors co-expressing different versions of the core protein (full-length, truncated and a version lacking residues 125-144) with GFP were constructed. Whilst these adenoviruses were being generated, experiments were carried out with an adenoviral vector expressing all the HCV structural proteins (Ad- CE1E2). These experiments revealed no effects of the core protein on DC phenotypic or functional maturation in response to LPS, TNFa or anti-CD40 stimulation. The core protein also had no effect on the ability of DCs to take up antigen and to stimulate allogenic and antigen-specific T cell responses. The core protein has also been proposed to alter the sensitivity of cells to apoptosis; experiments performed in this thesis did not support this, as the susceptibility of DCs to apoptosis induced via the Fas-Fas ligand, TRAIL and lymphotoxin pathways was not affected by core protein expression within these cells. The susceptibility of cells to lysis by natural killer cells and CD8+ cytotoxic cells was also not altered by expression of the core protein within them. These results do not support the core protein making a contribution to HCV persistence by immunomodulatory effects on DCs, although it remains possible that core protein expression at higher levels and/or at different intracellular sites within DCs could affect their functions.

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