Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide and thus represents a viral pandemic, one that is five times as widespread as infection with the human immunodeficiency virus type 1 (HIV-1). The institution of blood-screening measures in developed countries has decreased the risk of transfusion-associated hepatitis to a negligible level, but new cases continue to occur mainly as a result of injection-drug use and, to a lesser degree, through other means of percutaneous or mucous-membrane exposure. Progression to chronic disease occurs in the majority of HCV-infected persons, and infection with the virus has become the main indication . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM200107053450107?listPDF=true

Hepatitis C Virus Infection

FLAVIVIRUSES 1103 Background and Classification 1103 Structure and Physical Properties of the Virion 1104 Binding and Entry 1105 Genome Structure 1106 Translation and Proteolytic Processing 1107 Features of the Structural Proteins 1108 Features of the Nonstructural Proteins 1109 RNA Replication 1112 Membrane Reorganization and the Compartmentalization of Flavivirus Replication 1112 Assembly and Release of Particles from Flavivirus-infected Cells 1112 Host Resistance to Flavivirus Infection 1113

Flaviviridae :T he Viruses and Their Replication

Hepatitis C virus (HCV) infection is a global health problem affecting an estimated 170 million individuals worldwide. We report the identification of multiple independent adaptive mutations that cluster in the HCV nonstructural protein NS5A and confer increased replicative ability in vitro. Among these adaptive mutations were a single amino acid substitution that allowed HCV RNA replication in 10% of transfected hepatoma cells and a deletion of 47 amino acids encompassing the interferon (IFN) sensitivity determining region (ISDR). Independent of the ISDR, IFN-α rapidly inhibited HCV RNA replication in vitro. This work establishes a robust, cell-based system for genetic and functional analyses of HCV replication.

https://science.sciencemag.org/content/sci/290/5498/1972.full.pdf

Efficient initiation of HCV RNA replication in cell culture.

Hepatitis C virus (HCV) afflicts more than 170 million people worldwide causing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The recent development of complete cell-culture systems for HCV has accelerated the pace of hepatitis research. Specifically, these techniques have provided new insights into the virus lifecycle that are reviewed here. This should pave the way for developing bespoke and effective antiviral therapies and vaccines. Exciting progress has recently been made in understanding the replication of hepatitis C virus, a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The development of complete cell-culture systems should now enable the systematic dissection of the entire viral lifecycle, providing insights into the hitherto difficult-to-study early and late steps. These efforts have already translated into the identification of novel antiviral targets and the development of new therapeutic strategies, some of which are currently undergoing clinical evaluation.

Replication of hepatitis C virus

The action of interferons (IFNs) on virus-infected cells and surrounding tissues elicits an antiviral state that is characterized by the expression and antiviral activity of IFN-stimulated genes. In turn, viruses encode mechanisms to counteract the host response and support efficient viral replication, thereby minimizing the therapeutic antiviral power of IFNs. In this review, we discuss the interplay between the IFN system and four medically important and challenging viruses -- influenza, hepatitis C, herpes simplex and vaccinia -- to highlight the diversity of viral strategies. Understanding the complex network of cellular antiviral processes and virus-host interactions should aid in identifying new and common targets for the therapeutic intervention of virus infection. This effort must take advantage of the recent developments in functional genomics, bioinformatics and other emerging technologies.

Viruses and interferon: a fight for supremacy

Background A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) genotype 1b. The region spans amino acid residues 2209 to 2248 (NS5A2209–2248) of HCV-J, a strain of HCV-1b whose complete genomic sequence has been identified. We examined whether the NS5A2209–2248 sequence present before therapy could be used as a predictor of the response to interferon therapy in patients with chronic HCV-1b infection. Methods We retrospectively analyzed 84 patients with chronic HCV-1b infection who had received interferon alfa (total dose, 516 million to 880 million units) for six months. Pretreatment serum samples were analyzed. The amino acid sequence of NS5A2209–2248 was determined by direct sequencing of the HCV genome amplified by the polymerase chain reaction (PCR) and was compared with the established sequence for HCV-J. Results A complete response, as evidenced by the absence of HCV RNA in serum on nested reverse-transcription PCR ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199601113340203

Mutations in the Nonstructural Protein 5a Gene and Response to Interferon in Patients with Chronic Hepatitis C Virus 1b Infection

We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-lb was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferonsensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferonsensitive HCV. On the other hand, this region of interferonresistantHCV was identical to that of prototypeHCV genotype-lb (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus,HCV genotype-lb with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make

/pdf/sensitivity-to-interferon-is-conferred-by-amino-acid-437mjwxjy5.pdf

Sensitivity to Interferon is Conferred by Amino Acid Substitutions in the NS5A Region

Distribution of Cases of Hepatitis C Virus Infection by Subtypes and Results of Interferon Therapy in the Southern Region of Ibaraki Prefecture.

Two cases of malignant biliary obstruction successfully treated by percutanous transhepatic hepaticogastrostomy

We report a case of spontaneous remission of hepatocellular carcinoma in an 84‐year‐old woman who was managed in our best supportive care clinic. The tumor, once relapsed regardless of the application of conventional transcatheter arterial chemoembolization and radiofrequency ablation, regressed spontaneously within 4 months. The presence of an occlusive thrombus in the portal vein feeding to the site of the tumor suggests that the reduced blood supply might have caused tumor necrosis. Furthermore, the successful eradication of hepatitis C virus maintained performance status, and good nutrition might play other roles on it.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jgf2.588

Chikara Yamamoto

Papers

Mutations in the Nonstructural Protein 5a Gene and Response to Interferon in Patients with Chronic Hepatitis C Virus 1b Infection

Sensitivity to Interferon is Conferred by Amino Acid Substitutions in the NS5A Region

Distribution of Cases of Hepatitis C Virus Infection by Subtypes and Results of Interferon Therapy in the Southern Region of Ibaraki Prefecture.

Two cases of malignant biliary obstruction successfully treated by percutanous transhepatic hepaticogastrostomy

Spontaneous regression of hepatocellular carcinoma in a pure palliative care setting