benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Hepatitis-C--Chronic

Decreasing hepatocyte injury and death is an attractive therapeutic target in chronic hepatitis C and other liver diseases. Apoptotic cell death is a critical mechanism responsible for liver injury in hepatitis C, and contributes to hepatic fibrogenesis. At the cellular level, apoptosis is executed by a family of cysteine proteases termed caspases. Caspase inhibitors have been developed to inhibit these proteases and attenuate cellular apoptosis in vivo. By reducing hepatocyte apoptosis these agents have the potential to serve as hepatoprotective agents, minimizing liver injury and fibrosis. Studies on a variety of animal models, and time-limited studies in human patients with hepatitis C suggest these are promising therapeutic agents. However, although these agents hold promise, their usefulness requires further studies, especially longer duration studies using hepatic fibrogenesis as the end point before they can be considered further for the treatment of patients infected with the hepatitis C virus.

Topics: Amino Acid Chloromethyl Ketones; Antiviral Agents; Apoptosis; Caspase Inhibitors; Cysteine Proteinase Inhibitors; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Neoplasms

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity.

Topics: Adult; Amino Acid Chloromethyl Ketones; Antibodies, Monoclonal; Antigens, CD; Apoptosis; Apoptosis Regulatory Proteins; B7-H1 Antigen; Bcl-2-Like Protein 11; Cell Count; Cell Proliferation; Female; Hepatitis C, Chronic; Humans; Immunophenotyping; Interleukin-7 Receptor alpha Subunit; Liver; Lymphocyte Activation; Lymphocyte Count; Male; Membrane Proteins; Middle Aged; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Viral Load; Viral Nonstructural Proteins