Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility

University of Wisconsin-Madison, Madison, WI, United States.
Virology (Impact Factor: 3.32). 02/2013; 436(2). DOI: 10.1016/j.virol.2012.11.018
Source: PubMed


Hepatitis C virus (HCV) replication is limited by cyclophilin inhibitors but it remains unclear how viral genetic variations influence susceptibility to cyclosporine (cyclosporine A, CsA), a cyclophilin inhibitor. In this study HCV from liver transplant patients was sequenced before and after CsA exposure. Phenotypic analysis of NS5A sequence was performed by using HCV sub genomic replicon to determine CsA susceptibility. The data indicates an atypical proline at position 328 in NS5A causes increases CsA sensitivity both in the context of genotype 1a and 1b residues. Point mutants mimicking other naturally occurring residues at this position also increased (Ala) or decreased (Arg) replicon sensitivity to CsA relative to the typical threonine (genotype 1a) or serine (genotype 1b) at this position. This work has implications for treatment of HCV by cyclophilin inhibitors.

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Available from: Israrul Ansari, May 12, 2015
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    • "Whilst two related crystal structures have been determined with different dimeric interfaces for the N terminus of NS5A (Tellinghuisen et al., 2005; Love et al., 2009), the protein is also likely to have regions of disorder, and the overall tertiary and quaternary structure of NS5A in the cell is unknown. There has been a focus on NS5A for some time as a possible mediator of IFN resistance (Enomoto et al., 1996) as the target of host-cell cyclophilin inhibitors (Anasri & Striker, 2012; Ansari et al., 2013; Membreno et al., 2013) and more selective antivirals (Lok et al., 2012), 3These authors contributed equally to this publication. "
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