Dysregulation of interferon regulatory factors impairs the expression of immunostimulatory molecules in hepatitis C virus genotype 1-infected hepatocytes

Abstract

HCV genotype 1 infection downregulates IRF2 in hepatocytes attenuating hepatocellular expression of IL-7 and IL-15Rα. Our data reveal a new mechanism by which HCV abrogates specific T-cell responses and point to a novel therapeutic approach to stimulate anti-HCV immunity.

IRF-1 Promotes Liver Transplant Ischemia/Reperfusion Injury via Hepatocyte IL-15/IL-15Rα Production

“…Interestingly, our finding that hepatocytes are the major source of soluble IL-15/IL-15Rα complexes correlates well with a report (62) that identified hepatocytes as a new source of IL-7, another member of the common cytokine-receptor γ c family, that prolongs the survival of naïve and memory CD4 + and CD8 + T cells. Our findings are also consistent with those of a recent study (63) showing that IRF-1 regulates the induced expression of IL-15Rα by Huh7 (human hepatocellular carcinoma cell line) cells and that IRF-2, another member of the IRF family, controls basal expression of both IL-7 and IL-15Rα. The latter study shows that IRF-2 is significantly down-regulated in the liver in hepatitis C virus (HCV) infection and subsequently impaired expression of IL-7 and IL-15Rα in hepatocytes may explain poor HCV-specific CD8 + T cell responses, inability to eliminate HCV and perpetuation of infection (63).…”

“…Our findings are also consistent with those of a recent study (63) showing that IRF-1 regulates the induced expression of IL-15Rα by Huh7 (human hepatocellular carcinoma cell line) cells and that IRF-2, another member of the IRF family, controls basal expression of both IL-7 and IL-15Rα. The latter study shows that IRF-2 is significantly down-regulated in the liver in hepatitis C virus (HCV) infection and subsequently impaired expression of IL-7 and IL-15Rα in hepatocytes may explain poor HCV-specific CD8 + T cell responses, inability to eliminate HCV and perpetuation of infection (63). …”

A RIG-I 2CARD-MAVS200 Chimeric Protein Reconstitutes IFN-β Induction and Antiviral Response in Models Deficient in Type I IFN Response

“…In fact, Huh 7.0 cells expressing the HCV genome [14] are deficient in their ability to induce IFN-β in response to an RLR stimulus such as intracellular pIC in comparison to Huh7.0 control parental cells (Fig. 4B upper panel).…”

“…Rabbit Sirc cells used in this study have been described previously [13]. A549 cells were a kind gift from Heinrich Hoffmann (Microbiology Department, Icahn School of Medicine at Mount Sinai), HapT1 were a kind gift from Rubén Hernández-Alcoceba (CIMA, Universidad de Navarra), WHC17 were a kind gift from Dr. Michael Roggendorf (Center for Biomedical Biotechnology-Universitat Duisburg Essen), Huh7.0 cells expressing HCV genome were generated as described previously [14]. STAT1 KO and corresponding WT mouse embryo fibroblasts (WT MEFs and STAT1 KO MEFs respectively) as well as WT and KO IPS1 MEFs have been described previously [15, 16].…”

Especial Premio Nacional de Investigación en Medicina "Gregorio Marañón" 2014

“…La caracterización de la capacidad reguladora del metabolismo y hepatoprotectora de la citoquina cardiotrofina (CT1) (6), (7) y del factor de crecimiento FGF15 (8) ambos con posibles aplicaciones en la cirugía de trasplante. El estudio de los mecanismos moleculares implicados en la respuesta y la resistencia al tratamiento con interferón en los pacientes afectados por hepatitis C y la búsqueda de nuevas estrategias terapéuticas más efectivas (9). El desarrollo de diferentes y novedosas herramientas de terapia génica con múltiples aplicaciones (10).…”