Using this mouse model,

http://www.selleckchem.com/products/CP-690550.html erlotinib pre-treatment (5 days before infection) markedly reduced HCV-RNA (genotype 2a) levels by 90%. However, once treatment was discontinued, viral loads rebounded to those of the control-treated mice. These in vivo results hold much promise to potentially treat acute HCV infection in the setting of accidental exposure to HCV (i.e., needle-stick injury). The blocking of HCV entry in this scenario could prove invaluable to prevent the development of a chronic infection. Entry inhibitors may also prove useful for HCV-infected individuals undergoing liver transplantation, where reinfection of the donor tissue is inevitable and is associated with graft loss. In this setting, the use of RTK inhibitors and other entry inhibitors could potentially be used to prevent reinfection of the donor tissue. Though the in vivo studies by Lupberger et al. only assessed the efficacy of erlotinib on genotype 2a, in vitro the investigators demonstrated that siRNA knockdown of EGFR blocked HCV entry by multiple genotypes, including the most common genotype 1a, indicating that EGFR antagonism would block entry for all other HCV genotypes. Using the aforementioned murine

see more model system, it will be interesting to evaluate, in other studies, the use of PKIs in combination with the current standard of care for HCV, PEG-IFN-α/ribavirin combination therapy, and the recently approved NS3/4A serine protease inhibitors, selleck products boceprevir and telaprevir. EGFR has also been implicated in the life cycle of a number of other viruses. Most recently, it has been shown that when influenza A virus (IAV) binds to the plasma membrane surface, it causes the aggregation of lipid rafts, which, in turn, induces the clustering of RTKs (including EGFR).11 As a result of this clustering, activation of EGFR occurs, which is then thought to promote the

uptake of IAV via endocytosis.11 A number of oncogenic viruses (e.g., HBV, EBV, and AEV) have also been shown to hijack EGFR signaling and expression. This process is thought to be one of the mechanisms by which these oncogenic viruses induce cellular transformation.12 Although HCV does not appear to directly engage EGFR, the work of Lupberger et al. shows that EGFR signaling promotes HCV entry by the enhancement of both CD81/CLDN1 heterodimerization and fusion of the viral envelope with endosomal membranes without significantly perturbing hepatocyte polarity or tight junction integrity. Interestingly, recent studies have also indicated an interplay between EGFR signaling and HCV at other stages of the viral life cycle. In this context, the HCV NS5A protein has been shown to alter the distribution of EGFR and attenuate EGFR signaling.