Enhanced immune responses, PI3K/AKT and JAK/STAT signaling pathways following hepatitis C virus eradication by direct-acting antiviral therapy among Egyptian patients: a case control study

• Published in: Pathogens and disease 2021-04, Vol.79 (3)
• Main Authors: Ramadan, Haidi Karam-Allah, Badr, Gamal, Ramadan, Nancy K, Sayed, Aml
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adult; Aged; Aged, 80 and over; AKT protein; Antiviral agents; Antiviral Agents - therapeutic use; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - virology; Case-Control Studies; CD19 antigen; CD25 antigen; CD3 antigen; CD4 antigen; CD8 antigen; Cirrhosis; Cyclooxygenase-2; Cytokines - metabolism; Egypt; Female; Foxp3 protein; Gene Expression Regulation; Hepacivirus - drug effects; Hepacivirus - immunology; Hepatitis; Hepatitis C; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - virology; Hepatocellular carcinoma; Humans; Hypoxia-inducible factor 1a; IL-1β; Immune response; Immune system; Immunity; Interleukin 6; Interleukin 8; Janus Kinases - metabolism; Liver; Liver cancer; Liver cirrhosis; Liver Cirrhosis - immunology; Liver Cirrhosis - metabolism; Liver Cirrhosis - virology; Liver diseases; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - virology; Male; Middle Aged; PD-1 protein; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; Signaling; STAT Transcription Factors - metabolism; Stat3 protein; Stat5 protein; Sustained Virologic Response; Therapy; Tumor necrosis factor-α; Young Adult
• ISSN: 2049-632X; 2049-632X
• DOI: 10.1093/femspd/ftab008

ABSTRACT The use of direct-acting antivirals (DAAs) therapy for the treatment of hepatitis C virus (HCV) results in a high-sustained virological response (SVR) and subsequently alters liver immunologic environment. However, hepatocellular carcinoma (HCC) may occur after DAAs treatment. We aimed to clarify changes of immune responses, PI3K/AKT and JAK/STAT signaling pathways in HCV-induced liver diseases and HCC following DAAs treatment. Four cohorts were classified as chronic HCV patients, HCV-related cirrhosis without HCC, HCV-related cirrhosis and HCC, and healthy control group. The patient groups were further divided into treated or untreated with DAAs with SVR12. Increased percentages of CD3, CD8 and CD4, decreased CD4/FoxP3/CD25, CD8/PD-1 and CD19/PDL-1 were found in DAAs-treated patients in the three HCV groups. Following DAAs therapy, the levels of ROS, IL-1β, IL-6, IL-8 and TNF-α were significantly decreased in the three HCV groups. Treated HCV patients showed up regulation of p-AKT and p-STAT5 and down regulation of p-STAT3, HIF-1α and COX-2. In conclusion, DAAs enhance the immune response in chronic HCV and liver cirrhosis, hence our study is the first to show change in PI3K/AKT and JAK/STAT signaling pathways in different HCV-induced liver diseases after DAAs. In chronic HCV, DAAs have better impact on the immune response while in liver cirrhosis not all immune changes were prominent. Treatment with DAAs enhances the immune responses in chronic HCV patients through decreasing the pro-inflammatory signals; down regulating the expression levels of p-STAT3, HIF-1α and COX-2; and up regulating the expression levels of p-AKT and p-STAT5.