Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome.

Chronic hepatitis C is a lethal blood-borne infection often associated with a number of pathologies such as insulin resistance and other metabolic abnormalities. Insulin is a key hormone that regulates the expression of metabolic pathways and favors homeostasis. In this study, we demonstrated the molecular mechanism of hepatitis C virus (HCV) nonstructural protein 5A (NS5A)-induced metabolic dysregulation. We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance. Therefore, this study reveals that HCV NS5A is involved in enhanced gluconeogenic and lipogenic gene expression, which triggers metabolic abnormality and impairs insulin signaling pathway.

Current and future therapies for hepatitis C virus infection: from viral proteins to host targets.

Hepatitis C virus (HCV) infection is the most important problem across the world. It causes acute and chronic liver infection. Different approaches are in use to inhibit HCV infection, including small organic compounds, siRNA, shRNA and peptide inhibitors. This review article summarizes the current and future therapies for HCV infection. PubMed and Google Scholar were searched for articles published in English to give an insight into the current inhibitors against this life-threatening virus. HCV NS3/4A protease inhibitors and nucleoside/nucleotide inhibitors of NS5B polymerase are presently in the most progressive stage of clinical development, but they are linked with the development of resistance and viral breakthrough. Boceprevir and telaprevir are the two most important protease inhibitors that have been approved recently for the treatment of HCV infection. These two drugs are now the part of standard-of-care treatment (SOC). There are also many other drugs in phase III of clinical development. When exploring the various host-cell-targeting compounds, the most hopeful results have been demonstrated by cyclophilin inhibitors. The current SOC treatment of HCV infection is Peg-interferon, ribavirin and protease inhibitors (boceprevir or telaprevir). The future treatment of this life-threatening disease must involve combinations of therapies hitting multiple targets of HCV and host factors. It is strongly expected that the near future, treatment of HCV infection will be a combination of direct-acting agents (DAA) without the involvement of interferon to eliminate its side effects.

Transcript analysis of P2X receptors in PBMCs of chronic HCV patients: an insight into antiviral treatment response and HCV-induced pathogenesis.

BACKGROUND: After invasion of hepatocytes and immune cells, hepatitis C virus has the ability to escape from the host immune system, leading to the progression of disease into chronic infection with associated liver morbidities. Adenosine 5'triphosphate (ATP) is released in most of the pathological events from the affected cells and acts as a signaling molecule by binding to P2X receptors expressed on the host's immune cells and activates the immune system for pro-inflammatory response. Therefore, the present study was designed to analyze the transcript expression of the ionotropic purinergic P2X receptors on peripheral blood mononuclear cells (PBMCs) of chronic HCV patients to have study the immune responses mediated by P2X receptors in chronic HCV infections. METHODS: PBMCs were isolated from the collected blood samples. Transcript analysis of P2X receptors in PBMCs was done. The identity of amplified product was confirmed by sequencing PCR, while the quantification of the transcript expression was done by real time PCR. The relative expression of the P2X receptors was analyzed by unpaired Student's t test using GraphPad Prims 5 software. RESULTS: We found that out of seven isoforms of P2X receptors, P2X1, P2X4, P2X5, and P2X7 receptors are expressed on the PBMCs. P2X1 and P2X7 are significantly upregulated in treatment-naïve chronic HCV patients by 2.2- and 2.5-fold, respectively. However, only P2X7 expression is found increased by 2.7-fold in patients achieving sustained virological response (SVR) after antiviral treatment compared to healthy controls. The expression of P2X receptors remained unaltered in chronic HCV patients not responding to the treatment. CONCLUSION: The present study confirms the significant involvement of P2X receptors in the immune responses mediated by the PBMCs in the chronic HCV infection, which should be further investigated to devise strategies to augment the immune system against this chronic viral disease.

Development of murine models to study Hepatitis C virus induced liver pathogenesis.

Hepatitis C virus (HCV) is involved in different liver pathologies worldwide. In contemporary scenario, HCV treatment is lagging behind owing to absence of vaccines against virus. The only consideration for HCV treatment is pegylated interferon-alpha and ribavirin that results in sustained virological response in 50 % of patients. Two feasible hosts for HCV infection are chimpanzee and humans. For decades, chimpanzees are sole host to study HCV pathogenesis, but their use is limited due to ethical issues. The dilemma behind HCV therapy is the need of sustainable animal models that can help simulate in vivo conditions. We have assembled recent advances in animal models to study liver diseases for targeted therapy.