Hepatitis C virus infection and related liver disease: the quest for the best animal model

Abstract

Hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma (HCC) making the virus the most common cause of liver failure and transplantation. HCV is estimated to chronically affect 130 million individuals and to lead to more than 350,000 deaths per year worldwide. A vaccine is currently not available. The recently developed direct acting antivirals (DAAs) have markedly increased the efficacy of the standard of care but are not efficient enough to completely cure all chronically infected patients and their toxicity limits their use in patients with advanced liver disease, co-morbidity or transplant recipients. Because of the host restriction, which is limited to humans and non-human primates, in vivo study of HCV infection has been hampered since its discovery more than 20 years ago. The chimpanzee remains the most physiological model to study the innate and adaptive immune responses, but its use is ethically difficult and is now very restricted and regulated. The development of a small animal model that allows robust HCV infection has been achieved using chimeric liver immunodeficient mice, which are therefore not suitable for studying the adaptive immune responses. Nevertheless, these models allowed to go deeply in the comprehension of virus-host interactions and to assess different therapeutic approaches. The immunocompetent mouse models that were recently established by genetic humanization have shown an interesting improvement concerning the study of the immune responses but are still limited by the absence of the complete robust life cycle of the virus. In this review, we will focus on the relevant available animal models of HCV infection and their usefulness for deciphering the HCV life cycle and virus-induced liver disease, as well as for the development and evaluation of new therapeutics. We will also discuss the perspectives on future immunocompetent mouse models and the hurdles to their development.

Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents

“…Drug development was further supported by structural biology, which has provided high-resolution images of the structures of the virus, revealing additional crucial drug targets, such as NS3, NS5A, and NS5B. These images have allowed modelling of interactions between specific replication inhibitors and their targets [34,40,41] . With the advent of the NS5B polymerase inhibitor sofosbuvir (SFV) [42] , the NS3 PI simeprevir (SMV) [43] , and the NS5A replication inhibitor daclatasvir (DCV) [44] , three "second-wave" DAAs are now available and promise to be appropriate for LT patients, without severe adverse effects or negative interactions with immunosuppressants.…”

“…For decades, HCV has successfully escaped from all efforts to generate more efficient drugs, although research efforts have been intense [34] . Viral replication in vitro or in small-animal models could not be achieved, and functional studies were limited to chimpanzees [35][36][37] , what caused an important drawback to DAA development.…”

“…HCV subgenomes, which compose the nonstructural proteins NS3-NS5 linked to a selectable marker, can efficiently replicate in vitro. A few years later, a full-length isolate of HCV became available which can produce infectious viral particles in vitro [34,39] . The resulting improvement in the understanding of the viral life cycle opened the doors for the development of the first-generation DAAs.…”

“…Viral replication in vitro or in small-animal models could not be achieved, and functional studies were limited to chimpanzees [35][36][37] , what caused an important drawback to DAA development. The ultimate breakthrough for HCV drug development may be dated to establishment of the HCV replicon system, what was not earlier that 1999 [34,38] . HCV subgenomes, which compose the nonstructural proteins NS3-NS5 linked to a selectable marker, can efficiently replicate in vitro.…”

Progress in Vaccine Development for HCV Infection

“…Also the barriers that challenges vaccine research against HCV is the lack of small and suitable animal models for studying HCV pathogenesis and protective specific immunity. Nowadays, the chimpanzee is the only suitable infectious animal model with lots of ethical and financial obstacles to acquire [12]. Progression to chronic liver disease results from the ineffective weak immune response against the virus.…”