Lymphocytes and liver fibrosis in HIV & HCV coinfection

Abstract

Coinfection with HIV has an important impact on immunity against hepatitis C virus (HCV). In the present dissertation, phenotypes of lymphocytes derived from the peripheral blood of HCV-infected patients were studied into detail, with special attention to changes in phenotype of lymphocytes associated with HIV-coinfection and liver fibrosis. HCV-infection was associated with increased apoptosis of T lymphocytes in comparison to healthy controls. HCV-infection was also associated with increased cell activation and exhaustion of T lymphocytes and this was correlated to the level of HCV-viraemia, suggesting that HCV directly causes non-specific T cell activation and exhaustion in the periphery. T lymphocyte apoptosis, activation and exhaustion were independent of liver fibrosis. Together these findings suggest that, if left untreated, HCV might on long term contribute to dysfunction of T lymphocytes through non-specific immune activation, even in the absence of liver fibrosis. Coinfection with HIV was associated with even higher levels of peripheral T lymphocyte activation than HCV monoinfection. Natural killer (NK) cells are a type of lymphocytes belonging to the innate immune system. Of the NK cell subsets, the CD56dim NK cells have generally been considered as the primarily cytotoxic subset, whereas CD56bright NK cells are thought to merely exert cytokine-producing activity. Surprisingly, Feuth et al demonstrate that CD56bright NK cells typically display high levels of the cytotoxic molecule FasL on their surface. Furthermore, chronic infection with HCV is associated with upregulation of FasL as well as with the cytotoxic molecules granzyme B and perforin. Liver fibrosis has traditionally been diagnosed by liver biopsy, an invasive method with rare but severe complications. Transient elastography has recently been implemented as an non-invasive measurement for liver fibrosis. A retrospective analysis, presented in this dissertation, demonstrated that transient elastography has major clinical impact on clinical decision-making concerning treatment and follow-up of patients with viral hepatitis. Lastly, the CD4/CD8 T cell ratio was identified as an alternative non-invasive marker for liver fibrosis in HCV monoinfection. If this finding is to be confirmed in larger studies, the marker might be of value especially in settings where transient elastography is not available. Altogether, the studies presented in this dissertation shed new light on regulation of innate and adaptive immunity in HCV monoinfection and HIV-HCV coinfection and identify CD4/CD8 T cell ratio as a promising non-invasive marker of liver fibrosis in HCV monoinfection.