Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.

Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence

An estimated 3% of the global population are infected with hepatitis C virus (HCV), and the majority of these individuals will develop chronic liver disease. As with other chronic viruses, establishment of persistent infection requires that HCV-infected cells must be refractory to a range of pro-apoptotic stimuli. In response to oxidative stress, amplification of an outward K(+) current mediated by the Kv2.1 channel, precedes the onset of apoptosis. We show here that in human hepatoma cells either infected with HCV or harboring an HCV subgenomic replicon, oxidative stress failed to initiate apoptosis via Kv2.1. The HCV NS5A protein mediated this effect by inhibiting oxidative stress-induced p38 MAPK phosphorylation of Kv2.1. The inhibition of a host cell K(+) channel by a viral protein is a hitherto undescribed viral anti-apoptotic mechanism and represents a potential target for antiviral therapy.

Timing and depositional environments of a Middle Pleistocene glaciation of northeast England: New evidence from Warren House Gill, County Durham

At various times during the Quaternary, north-eastern England was a zone of confluence between dynamic ice lobes sourced from the Pennines, northern Scotland, the Cheviots, and Scandinavia. The region thus has some of the most complex exposures of Middle to Late Pleistocene sediments in Britain, with both interglacial and glacial sediments deposited in terrestrial and marine settings. We investigated sedimentary sequences exposed on the coastline of County Durham at Warren House Gill, and present a new model of British and Fennoscandian Ice Sheet interaction in the North Sea Basin during the Middle Pleistocene. The stratigraphy at Warren House Gill consists of a lower diamicton and upper estuarine sediments, both part of the Warren House Formation. They are separated from the overlying Weichselian Blackhall and Horden tills by a substantial unconformity. The lower diamicton of the Warren House Formation is re-interpreted here as an MIS 8 to 12 glaciomarine deposit containing ice-rafted lithics from north-eastern Scotland and the northeast North Sea, and is renamed the ‘Ash Gill Member’. It is dated by lithological comparison to the Easington Raised Beach, Middle Pleistocene Amino Acid Racemisation values, and indirectly by optically stimulated luminescence. The overlying shallow subaqueous sediments were deposited in an estuarine environment by suspension settling and bottom current activity. They are named the ‘Whitesides Member’, and form the uppermost member of the Warren House Formation. During glaciation, ice-rafted material was deposited in a marine embayment. There is no evidence of a grounded, onshore Scandinavian ice sheet in County Durham during MIS 6, which has long been held as the accepted stratigraphy. This has major implications for the currently accepted British Quaternary Stratigraphy. Combined with recent work on the Middle Pleistocene North Sea Drift from Norfolk, which is now suggested to have been deposited by a Scottish ice sheet, the presence of a Scandinavian ice sheet in eastern England at any time during the Quaternary is becoming increasingly doubtful.