However, a 30-day treatment of chimeric mice with erlotinib, a small molecule that specifically inhibits EGF-receptor

activity, did not prevent but only delayed the kinetics of infection. In conclusion, we show here that the human monoclonal antibody mAb16-71 can efficiently block in vitro and in vivo infection by multiple HCV genotypes. In addition, we demonstrate that blockade of SR-BI after infection can prevent rapid virus spread through the liver parenchyma, presumably by interfering with SR-BI-dependent cell-free as well as direct cell-to-cell HCV transmission. Therefore, targeting SR-BI may represent a superior strategy for anti-HCV immunotherapy to prevent the emergence of escape mutants and virus rebound during or following antiviral therapy, and to prevent allograft drug discovery infection in chronically infected HCV patients undergoing orthotopic

liver transplantation. We thank Dr. Veronique Stove and Yvonne Geybels for the analysis of mouse plasma and Dr. Robert H. Purcell (NIH) and Dr. Jens Bukh (NIH; CO-HEP, Copenhagen) for providing plasma from acutely infected chimpanzees. Additional Supporting Information may be found in the online version of this article. “
“During bile duct ligation (BDL), the growth of large cholangiocytes is regulated by the cyclic adenosine monophosphate (cAMP)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and is closely associated with increased secretin receptor (SR) expression. Although it has been suggested that SR modulates cholangiocyte growth, direct evidence for secretin-dependent proliferation is lacking. SR wild-type (WT) (SR+/+) or SR knockout (SR−/−) mice underwent sham surgery or BDL for 3 or 7 days. We evaluated MK-2206 manufacturer SR expression, cholangiocyte proliferation, and apoptosis in liver sections and proliferating cell nuclear antigen (PCNA) protein expression and ERK1/2 phosphorylation in purified large cholangiocytes from WT and SR−/− BDL mice. Normal WT mice were treated with secretin (2.5 nmoles/kg/day by way of osmotic minipumps for 1 week), and biliary mass was PJ34 HCl evaluated. Small and large cholangiocytes were

used to evaluate the in vitro effect of secretin (100 nM) on proliferation, protein kinase A (PKA) activity, and ERK1/2 phosphorylation. SR expression was also stably knocked down by short hairpin RNA, and basal and secretin-stimulated cAMP levels (a functional index of biliary growth) and proliferation were determined. SR was expressed by large cholangiocytes. Knockout of SR significantly decreased large cholangiocyte growth induced by BDL, which was associated with enhanced apoptosis. PCNA expression and ERK1/2 phosphorylation were decreased in large cholangiocytes from SR−/− BDL compared with WT BDL mice. In vivo administration of secretin to normal WT mice increased ductal mass. In vitro, secretin increased proliferation, PKA activity, and ERK1/2 phosphorylation of large cholangiocytes that was blocked by PKA and mitogen-activated protein kinase kinase inhibitors.