In addition, type III IFNs may contribute to overall antiviral activity. Whereas recombinant type I and III IFNs are known to have antiviral activity,17-19,
28 their relative effects on replication, based on the respective production levels in HCV infection, are not known. Culture supernatants of HCV-infected PHH showed a decrease of HCV replication by approximately 50%, which was the same level of antiviral activity that can be achieved with 200-500 pg/mL of recombinant type III IFN proteins, the maximum amount detected in PHH culture supernatants. This type III IFN concentration was also consistent with the peak type III IFN level (approximately 550 pg/mL of plasma) in acutely HCV-infected chimpanzees. However, the antiviral activity in the supernatant of HCV-infected PHH cultures was only CB-839 partially, reversed by neutralization of type III IFNs, and neutralization of type I IFNs had a lesser effect. There are at least two possible explanations. First, the complexity of HCV-induced ISGs is large and includes not only antiviral, but also proviral genes, such as ISG15 and ubiquitin-specific
peptidase 18, that may be induced in this setting.29, 30 Second, IFN-independent pathways may contribute to antiviral activity.31 The latter hypothesis is consistent with our in vivo results, where the increase in type III IFNs mirrored viremia, but was not associated with HCV clearance. An important final aspect R788 datasheet of this study is that all chimpanzees were monomorphic for the known human IL28B SNPs associated with spontaneous and treatment-induced outcome of HCV infection.12-15 This implies that human IL28B SNPs developed after the split of the human and chimpanzee lineages. Although chimpanzees may have other SNPs, our study shows that type III IFN levels in the liver
3-oxoacyl-(acyl-carrier-protein) reductase do not correlate with the spontaneous outcome of acute HCV infection. In addition, type III IFN levels from HCV-infected PHHs were not associated with IL28B SNPs. This corroborates a cross-sectional study of chronically HCV-infected humans in which intrahepatic IL28B mRNA levels were not affected by IL28B SNPs and not related to treatment-induced HCV clearance.32 Collectively, these data suggest that the identified IL28B SNPs affect the outcome of HCV infection by other, still to be determined, mechanisms. The authors thank Lauren Holz for her analysis of PHH purity and Su Hyung Park, Thomas O’Brien, and Sukanya Raghuraman for their discussion. Additional Supporting Information may be found in the online version of this article. “
“Deletion of glycine N-methyltransferase (GNMT), the main gene involved in liver S-adenosylmethionine (SAM) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis in mice.