Although combination therapy with interferon and ribavirin has improved the treatment for chronic hepatitis C virus (HCV) infection, the detailed anti-HCV effect of ribavirin in clinical concentrations remains uncertain. To detect the anti-HCV effect of ribavirin in lower concentrations, a sensitive and accurate assay system was developed using the reporter replicon system with an HCV genotype 2a subgenomic replicon (clone JFH-1) that exhibits robust replication in various cell lines. This reporter replicon was generated by introducing the luciferase reporter gene (instead of the neomycin resistance gene) into the subgenomic JFH-1 replicon. To assess the replication of this reporter replicon, luciferase activity was measured serially up to day 3 after transient transfection of Huh7 cells. The luciferase activity increased exponentially over the time course of the experiment. After adjustment for transfection efficiency and transfected cell viability, the impacts of interferon and ribavirin were determined. The administration of interferon and ribavirin resulted in dosedependent suppression of replicon RNA replications. The 50% inhibitory concentration of interferon and ribavirin was 1.80 IU/ml and 3.70 g/ml, respectively. In clinical concentrations, replications were reduced to 0.09% and 53.74% by interferon (100 IU/ml) and ribavirin (3 g/ml), respectively. Combination use of ribavirin and interferon enhanced the anti-HCV effect of interferon by 1.46-to 1.62-fold. In conclusion, we developed an accurate and sensitive replicon system, and the antivirus effect of interferon and ribavirin was easily detected within their clinical concentrations by this replicon system. This system will provide a powerful tool for screening new antiviral compounds against HCV.Hepatitis C virus (HCV) is a major public health problem, infecting an estimated 170 million people worldwide. HCV causes chronic liver diseases, including cirrhosis and hepatocellular carcinoma, because most patients fail to clear the virus and the persistent infection that follows (1,11,20). Current therapy for HCV-related chronic hepatitis is based on the use of interferon (IFN). However, virus clearance rates are limited to approximately 10 to 20% of cases treated with IFN only (9,23,26). Combination therapy with IFN and ribavirin improves the HCV clearance rate, although the molecular mechanism responsible for this improvement is not yet fully understood (23,25,26). However, some direct antiviral mechanisms of ribavirin have been proposed (19). One possible mechanism is the direct inhibition of HCV RNA-dependent RNA polymerase, and another possibility is the RNA mutagen effect that drives a rapidly mutating RNA virus over the threshold to "error catastrophe." The detection of these direct anti-HCV effects has been hampered by the lack of an appropriate sensitive system for evaluating HCV replication.Although HCV belongs to the Flaviviridae family and has a genome structure similar to those of the other flaviviruses (3, 27), efficient cell culture systems a...
The c-axis resistivity (p, ) and its temperature dependence of highly oriented pyrolytic graphite have been studied in connection with the characteristic stacking-fault structure. In order to account for the observations, the pioneering theory of Ono on the tunneling conduction through the stacking-fault planes is reformulated using the concept of effective fault spacing. It is proposed further to add two mechanisms to the Ono theory; one is interlayer charge transfer through the impurity-assisted hopping of carriers similar to that previously considered for graphite intercalation compounds, and the other is thermal excitation of carriers across the low potential barrier formed on each fault plane. All the data have been satisfactorily reproduced by the curve fitting based on the formula consisting of these three conduction components. Also, the change of p, in the presence of high pressure is pointed out to be qualitatively explainable in terms of the tunneling associated with the pressure dependence of Slonczewski-Weiss band parameters.
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