Advances in experimental systems to study hepatitis C virus in vitro and in vivo

Abstract

Hepatitis C virus (HCV) represents a global health concern affecting over 185 million people worldwide. Chronic HCV infection causes liver fibrosis and cirrhosis and is the leading indication for liver transplantation. Recent advances in the field of direct-acting antiviral drugs (DAAs) promise a cure for HCV in over 90% of cases that will get access to these expensive treatments. Nevertheless, the lack of a protective vaccine and likely emergence of drug-resistant viral variants call for further studies of HCV biology. With chimpanzees being for a long time the only non-human in vivo model of HCV infection, strong efforts were put into establishing in vitro experimental systems. The initial models only enabled to study specific aspects of the HCV life cycle, such as viral replication with the subgenomic replicon and entry using HCV pseudotyped particles (HCVpp). Subsequent development of protocols to grow infectious HCV particles in cell-culture (HCVcc) ignited investigations on the full cycle of HCV infection and the virus-host interactions required for virus propagation. More recently, small animal models permissive to HCV were generated that allowed in vivo testing of novel antiviral therapies as well as vaccine candidates. This review provides an overview of the currently available in vitro and in vivo experimental systems to study HCV biology. Particular emphasis is given to how these model systems furthered our understanding of virus-host interactions, viral pathogenesis and immunological responses to HCV infection, as well as drug and vaccine development.

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

“…Infection with HCV holds a high risk of causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma, resulting in 350,000 human deaths each year. Although current developed direct-acting antivirals (DAAs) are capable of effectively eradicating HCV infection from patients, several hurdles remain, including high costs, emergence of drug resistance, and side effects (2). Treatment with DAAs in a portion of HCV patients suffering from advanced liver disease does not eliminate the risk of hepatocellular carcinoma.…”

Ralf Bartenschlager, Charles Rice, and Michael Sofia are honored with the 2016 Lasker~DeBakey Clinical Medical Research Award

“…Additionally, mutations within Huh-7 cells were identified that improved the ability of the cells to replicate HCV replicons (20,21). The identification of both viral and host cell mutations that allowed for a highly permissive environment would pave the way for the development of replicons representing all HCV genotypes and for the establishment of other cell lines that support HCV replication (22). There was excitement with the establishment of these highly permissible replicon systems; it was initially thought that simply adding back the structural components of the HCV genome would be enough to establish infectious particles.…”

“…Finally, the full life cycle of HCV could be studied, leading to a better understanding of the host and viral factors required for replication and viral entry into host cells (for reviews, see refs. 22,28,29).…”

Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1

“…Our insight in the HCV life cycle was hampered for a long time but the development of the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems paved the way for a more comprehensive exploration of virus infectivity (Hsu et al, 2003; Wakita et al, 2005). Both systems are now widely used for studying HCV entry and screening for viral inhibitors (Catanese and Dorner, 2015). The envelope proteins E1 and E2 are highly glycosylated membrane-associated proteins consisting of an N-terminal ectodomain and a C-terminal transmembrane domain.…”