Cellular factors involved in the hepatitis C virus life cycle

The hepatitis C virus(HCV),an obligatory intracellular pathogen,highly depends on its host cells to propagate successfully.The HCV life cycle can be simply divided into several stages including viral entry,protein translation,RNA replication,viral assembly and release.Hundreds of cellular factors involved in the HCV life cycle have been identified over more than thirty years of research.Characterization of these cellular factors has provided extensive insight into HCV replication strategies.Some of these cellular factors are targets for anti-HCV therapies.In this review,we summarize the well-characterized and recently identified cellular factors functioning at each stage of the HCV life cycle.

Assembly and release of infectious hepatitis C virus involving unusual organization of the secretory pathway

AIM: To determine if calnexin(CANX), RAB1 and alphatubulin were involved in the production of hepatitis C virus(HCV) particles by baby hamster kidney-West Nile virus(BHK-WNV) cells. METHODS: Using a si RNA-based approach complemented with immuno-fluorescence confocal microscope and Western blot studies, we examined the roles of CANX, RAB1 and alpha-tubulin in the production of HCV particles by permissive BHK-WNV cells expressing HCV structural proteins or the full-length genome of HCV genotype 1a. Immuno-fluorescence studies in producer cells were performed with monoclonal antibodies against HCV structural proteins, as well as immunoglobulin from the serum of a patient recently cured from an HCV infection of same genotype. The cellular compartment stained by the serum immunoglobulin was also observedin thin section transmission electron microscopy. These findings were compared with the JFH-1 strain/Huh-7.5 cell model.RESULTS: We found that CANX was necessary for the production of HCV particles by BHK-WNV cells. This process involved the recruitment of a subset of HCV proteins, detected by immunoglobulin of an HCV-cured patient, in a compartment of rearranged membranes bypassing the endoplasmic reticulum-Golgi intermediary compartment and surrounded by mitochondria. It also involved the maturation of N-linked glycans on HCV envelope proteins, which was required for assembly and/or secretion of HCV particles. The formation of this specialized compartment required RAB1; upon expression of HCV structural genes, this compartment developed large vesicles with viral particles. RAB1 and alpha-tubulin were required for the release of HCV particles. These cellular factors were also involved in the production of HCVcc in the JFH-1 strain/Huh-7.5 cell system, which involves HCV RNA replication. The secretion of HCV particles by BHK-WNV cells presents similarities with a pathway involving caspase-1; a caspase-1 inhibitor was found to suppress the production of HCV particles from a full-length genome.CONCLUSION: Prior activity of the WNV subgenomic replicon in BHK-21 cells promoted re-wiring of host factors for the assembly and release of infectious HCV in a caspase-1-dependent mechanism.

Wave Propagation Characteristics in Thick Conventional and Auxetic Cellular Plates

Based on Mindlin plate models and Kirchhoff plate models,this study was concerned with the wave propagation characteristics in thick conventional and auxetic cellular structures,with the objective to clarify the effects of negative Poisson＇s ratio,shear factor and orthotropic mechanical properties on the dynamic behaviors of thick plates.Numerical results revealed that the predictions using variable shear factor in Mindlin plate models resulted in high wave frequencies,which were more significant for plates with negative values of Poisson＇s ratio.The present study can be useful for the design of critical applications by varying the values of Poisson＇s ratio.

Tumor microenvironment of cancer stem cells:Perspectives on cancer stem cell targeting

There are few tumor cell subpopulations with stem cell characteristics in tumor tis-sue,defined as cancer stem cells(CSCs)or cancer stem-like cells(CSLCs),which can recon-struct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation.The microenvironment that CsCs depend on consists of various cellular components and corresponding medium components.Among these factors existing at a variety of levels and forms,cytokine networks and numerous signal pathways play an important role in signaling transduction.These factors promote or maintain cancer cell stem-ness,and participate in cancer recurrence,metastasis,and resistance.This review aims to summarize the recent molecular data concerning the multilayered relationship between CsCs and CsC-favorable microenvironments.We also discuss the therapeutic implications of target-ing this synergistic interplay,hoping to give an insight into targeting cancer cell stemness for tumortherapyandprognosis.