Host heat shock cognate 70 (Hsc70) protein is packaged into hepatitis C viral (HCV) particles as a structural component of the virus in the assembly process. It helps HCV RNA release into the cytoplasm in the next infection cycle. The goal of this study is to investigate whether chemically down-regulating host Hsc70 expression could be a novel strategy to interrupt HCV replication. Compounds were screened with an Hsc70 messenger RNA (mRNA) assay. IMB-DM122 was found to be an effective and safe inhibitor for Hsc70 mRNA/protein expression in human hepatocytes. IMB-DM122 inhibited HCV replication through destabilization of Hsc70 mRNA, and the half-life of host Hsc70 mRNA was reduced by 78% after the compound treatment. The Hsc70 mRNA 3 0 untranslated region sequence is the element responsible for the effect of IMB-DM122 on Hsc70 mRNA. The compound appears to be highly efficient in inhibiting Hsc70-related HCV replication. Treatment of the HCV-infected hepatocytes with IMB-DM122 reduced the virion encapsidation of Hsc70, and therefore disrupted HCV replication and the infection cycle. IMB-DM122 showed considerable good safety in vitro as well as in vivo with no indication of harmful effect on liver and kidney functions. Conclusion: Hsc70 might be a new drug target and mechanism to inhibit HCV proliferation. (HEPATOLOGY 2010;52:845-853) H epatitis C virus (HCV) is a single-stranded RNA virus belonging to the Flaviviridae family. 1 Current standard therapy for hepatitis C in the clinic is the combination of pegylated-interferon with ribavirin. 2,3 The regimen is effective in 40%-50% of patients infected with HCV genotype 1 and is associated with significant side effects. 3,4 Recently, telaprevir and boceprevir, two peptidomimetic inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) protease, have shown great promise in clinical patients. [5][6][7][8] However, antiviral therapy targeting specific HCV proteases has caused emergence of drug-resistant mutations, 9-12 and thus, new mechanisms for anti-HCV drugs are highly desirable.Human heat shock cognate 70 (Hsc70, or heat shock protein A8) is a cytoplasm adenosine triphosphate-binding protein with 646 amino acids. 13 It is a member of the heat shock protein 70 (Hsp70) family with the gene located in chromosome 11. 14 The functions of Hsc70 protein in normal cells are complicated and remain to be clarified. 15 Virology research has shown that Hsc70 might play a role in regulating virion capsid assembly. 16 A recent study by Parent et al. demonstrated that host Hsc70 is part of the HCV particle. 17 They showed Hsc70 interaction HPD (HisPro-Asp) motif present on the E2 envelope of HCV (the J6/JFH [Japanese fulminant hepatitis] strain) and coexistence of Hsc70 with the HCV core and E2 proteins around lipid droplets in the infected cells.

Gliomas grading is important for treatment plan; we aimed to investigate the application of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in gliomas grading, by comparing with the three-dimensional pseudocontinuous arterial spin labeling (3D pCASL). 24 patients (13 high grade gliomas and 11 low grade gliomas) underwent IVIM DWI and 3D pCASL imaging before operation; maps of fast diffusion coefficient (D ∗), slow diffusion coefficient (D), fractional perfusion-related volume (f), and apparent diffusion coefficient (ADC) as well as cerebral blood flow (CBF) were calculated and then coregistered to generate the corresponding parameter values. We found CBF and D ∗ were higher in the high grade gliomas, whereas ADC, D, and f were lower (all P < 0.05). In differentiating the high from low grade gliomas, the maximum areas under the curves (AUC) of D ∗, CBF, and ADC were 0.857, 0.85, and 0.902, respectively. CBF was negatively correlated with f in tumor (r = −0.619, P = 0.001). ADC was positively correlated with D in both tumor and white matter (r = 0.887, P = 0.000 and r = 0.824, P = 0.000, resp.). There was no correlation between CBF and D ∗ in both tumor and white matter (P > 0.05). IVIM DWI showed more efficiency than 3D pCASL but less validity than conventional DWI in differentiating the high from low grade gliomas.

Host cellular factor apolipoprotein B messenger RNA (mRNA)-editing enzyme catalytic polypeptide-like 3G (hA3G) is a cytidine deaminase that inhibits a group of viruses including human immunodeficiency virus-1 (HIV-1). In the continuation of our research on hA3G, we found that hA3G stabilizing compounds significantly inhibited hepatitis C virus (HCV) replication. Therefore, this study investigated the role of hA3G in HCV replication. Introduction of external hA3G into HCV-infected Huh7.5 human hepatocytes inhibited HCV replication; knockdown of endogenous hA3G enhanced HCV replication. Exogenous HIV-1 virion infectivity factor (Vif) decreased intracellular hA3G and therefore enhanced HCV proliferation, suggesting that the presence of Vif might be an explanation for the HIV-1/HCV coinfection often observed in HIV-1(1) individuals. Treatment of the HCV-infected Huh7.5 cells with RN-5 or IMB-26, two known hA3G stabilizing compounds, increased intracellular hA3G and accordingly inhibited HCV replication. The compounds inhibit HCV through increasing the level of hA3G incorporated into HCV particles, but not through inhibiting HCV enzymes. However, G/A hypermutation in the HCV genome were not detected, suggesting a new antiviral mechanism of hA3G in HCV, different from that in HIV-1. Stabilization of hA3G by RN-5 was safe in vivo. Conclusion: hA3G appears to be a cellular restrict factor against HCV and could be a potential target for drug discovery.