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Objective: Chronically HCV-infected orthotopic liver transplantation (OLT) recipients appear to have improved outcomes when their immunosuppressive regimen includes a mammalian target of rapamycin (mTOR) inhibitor. The mechanism underlying this observation is unknown.
Design: We used virological assays to investigate mTOR signalling on the HCV replication cycle. Furthermore, we analysed HCV RNA levels of 42 HCV-positive transplanted patients treated with an mTOR inhibitor as part of their immunosuppressive regimen.
Results: The mTOR inhibitor rapamycin was found to be a potent inhibitor for HCV RNA replication in Huh-7.5 cells as well as primary human hepatocytes. Half-maximal inhibition was observed at 0.01 µg/mL, a concentration that is in the range of serum levels seen in transplant recipients and does not affect cell proliferation. Early replication cycle steps such as cell entry and RNA translation were not affected. Knockdown of raptor, an essential component of mTORC1, but not rictor, an essential component of mTORC2, inhibited viral RNA replication. In addition, overexpression of raptor led to higher viral RNA replication, demonstrating that mTORC1, but not mTORC2, is required for HCV RNA replication. In 42 HCV-infected liver-transplanted or kidney-transplanted patients who were switched to an mTOR inhibitor, we could verify that mTOR inhibition decreased HCV RNA levels in vivo.
Conclusions: Our data identify mTORC1 as a novel HCV replication factor. These findings suggest an underlying mechanism for the observed benefits of mTOR inhibition in HCV-positive OLT recipients and potentiate further investigation of mTOR-containing regimens in HCV-positive recipients of solid organ transplants.
Improving nomenclatural consistency: a decade of experience in the World Register of Marine Species
(2017)
The World Register of Marine species (WoRMS) has been established for a decade. The early history of the database involved compilation of existing global and regional species registers. This aggregation, combined with changes to data types and the changing needs of WoRMS users, has resulted in an evolution of data-entry consistency over time. With the task of aggregating the accepted species names for all marine species approaching completion, our focus has shifted to improving the consistency and quality of data held while keeping pace with the addition of > 2000 new marine species described annually. This paper defines priorities and longer-term aims that promote standardisation within and interoperability among biodiversity databases, provides editors with further information on how to input nomenclatural data in a standardised way and clarifies for users of WoRMS how and why names are represented as they are. We 1) explain the categories of names included; 2) list standard reasons used to explain why a name is considered ‘unaccepted’ or ‘uncertain’; 3) present and explain the more difficult situations encountered; 4) describe categories of sources and notes linked to a taxon; and 5) recommend how type material, type locality and environmental information should be entered.