To understand IFN resistance in vivo, we examined the dynamic responses to human IFN (hIFN)-alfa, -gamma and consensus IFN in the chimpanzee model. In vitro study with peripheral blood mononuclear cells (PBMCs) of naive chimpanzees and healthy human donors showed that chimpanzee responded less well than human to hIFNs. Naive and HCV-infected chimpanzees were treated with hIFNs using higher doses to compensate for the lower efficacy of hIFNs in chimpanzees. The in vivo responses of PBMCs to all three IFNs were much lower in the HCV-infected chimpanzees than those in the naive chimpanzees. The difference was more dramatic in the liver as the hepatic IFN-induced gene inductions were barely detectable in the infected animals. Assessment of various IFN signaling inhibitors showed that following IFN administration, the expression of suppressor of cytokine signaling 3 (SOCS3) was significantly upregulated, possibly through the induction of IL-6, in the liver of HCV-infected chimpanzees. In conclusion, these data indicate a defective response, particularly in the liver, to IFNs in HCV-infected chimpanzees, and this defect is possibly mediated through the activation of SOCS3. Further study on the inhibitory mechanism of IFN effector pathway by HCV infection in chimpanzee may provide novel insights into the clinical issue of nonresponse to IFN therapy.? ? To further explore the mechanisms of IFN action and resistance in HCV patients, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group patients received either peginterferon alfa-2a alone or ribavirin for 72 hours and peginterferon-alfa 24 hours prior to biopsy. Patients were grouped into rapid responders (RR) with >2-log drop and slow responders (SR) with <2-log drop in HCV RNA by week 4. Pre-treatment biopsy specimens were obtained from a matched control group. Pre-treatment patients were grouped as RR or SR based on subsequent treatment response. Gene expression profiling was performed using Affymetrix microarray technology. Known ISGs were induced in treated patients. In the pre-treatment group, future slow responders (SR) had higher pretreatment ISG expression than rapid responders (RR). On treatment, RR and SR had similar absolute ISG expression but when corrected for baseline expression using the pre-treatment group, RR had marked induction of ISGs while SR showed up-regulation of IFN-inhibitory pathways. Patients pretreated with ribavirin had heightened induction of IFN-related genes as well as down-regulation of genes involved in IFN-inhibition and hepatic stellate cell (HSC) activation. These data suggest that ISG inducibility is important for treatment response and ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.
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