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Abstract Details
Low Oxygen Tension Enhances Hepatitis C Virus Replication
Vassilaki N, Kalliampakou KI, Kotta-Loizou I, Befani C, Liakos P, Simos G, Mentis AF, Kalliaropoulos A, Doumba PP, Smirlis D, Foka P, Bauhofer O, Poenisch M, Windisch MP, Lee ME, Koskinas J, Bartenschlager R, Mavromara P. J Virol. 2012 Dec 26. [Epub ahead of print]
Source
Molecular Virology, Hellenic Pasteur Institute (HPI), Athens, Greece.
Abstract
Low oxygen tension exerts a significant effect on the replication of several DNA and RNA viruses in cultured cells. In vitro propagation of the hepatitis C virus (HCV) has thus far been studied under atmospheric oxygen levels despite the fact that the liver tissue microenvironment is hypoxic. In this study, we investigated the efficiency of HCV production in actively dividing or differentiated human hepatoma cells cultured under low or atmospheric O(2) tensions. By using both HCV replicons and infection-based assays, low oxygen condition was found to enhance HCV RNA replication whereas virus entry and RNA translation were not affected. Hypoxia signaling pathway-focused DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR) analyses revealed an upregulation of genes related to hypoxic stress, glycolytic metabolism, cell growth and proliferation when cells were kept under low (3% v/v) O(2) tension, likely reflecting cell adaptation to anaerobic conditions. Interestingly, hypoxia-mediated enhancement of HCV replication correlated directly with the increase in anaerobic glycolysis and creatine kinase B (CKB) activity leading to elevated ATP production. Surprisingly, activation of hypoxia-inducible factor-α (HIF-α) was not involved in the elevation of HCV replication. Instead, a number of oncogenes, known to be associated with glycolysis were upregulated and evidence was obtained that these oncogenes contribute to hypoxia-mediated enhancement of HCV replication. Finally, in liver biopsies of HCV-infected patients, the levels of hypoxia and anaerobic metabolism markers correlated with HCV RNA levels. These results provide new insights into the impact of O(2) tension on the intricate HCV - host cell interaction.