Use this URL to cite or link to this record in EThOS:
Title: Interactions of HIV-1 and hepatitis C virus with iron metabolism
Author: Eddowes, Lucy A.
ISNI:       0000 0004 2725 8327
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2010
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
Iron is essential for almost all biological systems and its metabolism is perturbed during infection. Clinical evidence suggests that elevated iron status correlates with a poor prognosis in HIV-1 infection. Four steps of the HIV-1 life cycle are thought to be iron dependent: reverse transcription, transcription, nuclear export of mRNA and virion assembly. The HIV protein Nef downregulates the haemochromatosis protein HFE in vitro, and iron chelators can inhibit HIV-1 replication. Given the evidence that iron can affect HIV -1 disease course and replication we investigated HIV -1 replication in monocyte-derived macrophages (MDMs) from both HFE wild type and C282Y-haemochromatosis patients. Our data from multiple patients suggests that the extent of HIV -1 replication is independent of HFE genotype in MDMs. Supplementation with the iron chelator DFO and the iron salt F AC both inhibited HIV-1 replication. Infecting differentiated U937 cells as a model system to avoid person to person variation gave inconsistent results when different viral strains and-experimental conditions were used. Changes in iron distribution during HIV-1 infection may be mediated by hepcidin. Hepcidin can be produced as part of the innate immune response which is mediated by the recognition of pathogen- associated molecular patterns (PAMPs) by a family of proteins including the Toll-like receptors (TLRs). We found that HIV-derived TLR7/8 ligands that stimulate the production ofTNFa. and IL6 in PBMCs and neutrophils does not result in a significant change in hepcidin expression whereas flagellin, a TLR5 ligand, induces TNFa., IL6 and hepcidin expression. This suggests that the changes in iron distribution may be more strongly influenced by IL6-mediated hepcidin induction in the liver or more directly by bacterial products that can cross the compromised gut mucosa during HIV-1 infection. Iron accumulation is an important eo-morbidity factor in Hepatitis C virus (HCV) infection. Chronic HCV patients have inappropriately low hepcidin expression which may explain their iron overload. Reduced hepcidin also causes the iron loading disorder hereditary haemochromatosis (HH). Genetic mutations underlying HH disrupt bone morphogenetic protein (BMP) dependent signalling pathways that control hepcidin synthesis. We investigated whether HCV was affecting the BMP/SMAD pathway, dampening down the signal for hepcidin induction, using an infectious HCV in vitro model. We found hepcidin induction by BMP6 but not BMP9 to be impaired by HCV infection. HJV, the BMP6 coreceptor, is downregulated and both SMAD6 and SMAD7 which suppress BMP signalling are upregulated in HCV infected cultures. HCV also increases expression of TNFa., and in vitro the inhibitory effect of HCV on BMP signalling can be mimicked by TNFa. In addition, supplementing cultures with an anti- TNFa. antibody restored hepcidin expression in response to BMP6. These observations were followed up in HCV patient liver biopsies from two separate cohorts. Both cohorts had lower hepcidin mRNA expression compared to a control group, consistent with other published clinical studies. HJV and ID1 mRNA was suppressed in biopsies from non-responders in the cohort with more severe disease whereas SMAD6 mRNA expression was raised in the biopsies from the cohort with mild disease. This demonstrates that the BMP/SMAD pathway can be disrupted by HCV infection and may explain the inappropriately low hepcidin expression found in vivo. Understanding the mechanism behind the hepcidin suppression found in HCV patients may suggest new therapies to prevent their iron overload thereby slowing their progression to cirrhosis and hepatocellular carcinoma.
Supervisor: Drakesmith, A. H. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available