New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets

Abstract

Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review.

Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves

“…Moreover, recent approval of other direct-acting antivirals (DAA), including NS5A inhibitors, can further improve the SVR rate. However, they are not equally effective for all of the seven HCV genotypes and, more importantly, serious adverse effects are observed with some patients [5,8]. This highlights the need for a new alternative and/or complementary agent(s) for treatment of HCV.…”

High-yield production of a chimeric glycoprotein based on permuted E1 and E2 HCV envelope ectodomains

“…E2 is the primary glycoprotein responsible for the interaction with cellular receptors including heparan sulfate, the tetraspanin CD81, the scavenger receptor BI, the tight junction proteins claudin-1 and occludin, the Niemann-Pic C1-like 1 cholesterol absorption receptor and other factors (reviewed in (Ploss and Dubuisson, 2012), while little is known about the exact role of E1 protein. It has been shown that E1…”

Production and characterization of the ectodomain of E2 envelope glycoprotein of hepatitis C virus folded in the presence of full-length E1 glycoprotein

“…In the search of a future first vaccine for HCV, a possible strategy is to abolish the initial steps of the HCV infection. In this regard, HCV entry is a highly orchestrated process mediated by viral envelope glycoproteins E1 and E2 and several host factors including heparan sulfate, the tetraspanin CD81, the scavenger receptor BI, the tight junction proteins claudin-1 and occludin, the Niemann-Pic C1-like 1 cholesterol absorption receptor and other factors (reviewed in [2]) .…”