نبذة مختصرة : Chronic hepatitis C can lead to life threatening conditions like cirrhosis, liver failure and hepatocellular carcinoma. There are an estimated 170 million chronic carriers of the hepatitis C virus (HCV) world wide, making it a serious global health problem. 70-90 % of the newly infected individuals will fail to clear the virus and develop chronic hepatitis. There is no vaccine, and the only treatment available is a long-term combination therapy of pegylated interferon-á (peg-IFN-á) and Ribavirine (RBV). Unfortunately, this regiment cannot be given to all patients, and of the treated individuals only 50-80 % will succeed in clearing. the virus. Therefore, more efficient treatment approaches are needed. To achieve them, a deeper understanding of the virus and its interaction with the host is necessary. This thesis will focus on two aspects of the HCV life cycle; the translation and replication of the virus genome. In the first section, viral translation mediated by the internal ribosome entry site (IRES) of the HCV genotype 3 and its relation to treatment response was studied. A Pakistani cohort of approximately 144 chronic HCV patients was treated with IFN-á and RBV. Follow up one year post treatment showed 70% sustained responders (SR) and 30% nonresponders (NR) (depicting if the virus was cleared or not). Substantial differences in the IRES nucleic acid sequence between the two groups were observed. This prompted analyses of translation efficiencies of IRES regions derived from 15 SR and 7 NR randomly selected patients. The SR derived IRES displayed significantly lower translation efficiencies than those of the NR group (29.7 ± 13 vs. 69.4 ± 22; P < 0.01). This difference may be a consequence of more disrupted IRES tertiary structure in the SR group compared to the NR group. The results indicate that a correlation between the IRES sequence and the therapeutic outcome may serve as a prediction model of treatment outcome for HCV genotype 3. However, further studies are needed to establish such a model, and to ...
Relation: I. Yasmeen A, Hamid S, Granath FN, Lindstrom H, Elliott RM, Siddiqui AA, Persson MA (2006). Correlation between translation efficiency and outcome of combination therapy in chronic hepatitis C genotype 3. J Viral Hepat. 13(2): 87-95. ::doi::10.1111/j.1365-2893.2005.00660.x ::pmid::16436126 ::isi::000234855300003; II. Lundin M, Lindstrom H, Gronwall C, Persson MA (2006). Dual topology of the processed hepatitis C virus protein NS4B in influenced by the NS5A protein. J Gen Virol. [Accepted] ::doi::10.1099/vir.0.82211-0 ::pmid::17030859 ::isi::000241542100015; III. Lindstrom H, Lundin M, Persson MA (2006). N-terminal translocation, oligomerization, and membrane rearragements of the HCV protein NS4B are interlinked. [Manuscript]; IV. Lindstrom H, Lundin M, Haggstrom S, Persson MA (2006). Mutations of the Hepatitis C virus protein NS4B on either side of the ER membrane affect the efficiency of subgenomic replicons. Virus Res. [Accepted] ::doi::10.1016/j.virusres.2006.05.008 ::pmid::16806556 ::isi::000241644400008; 91-7140-875-4; 20060908lind; http://hdl.handle.net/10616/39101
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