Hepatitis C virus cell entry: a target for novel antiviral strategies to address limitations of direct acting antivirals

Abstract

Hepatitis C virus (HCV) infection remains a major global health problem, with 130-170 million chronically infected individuals at risk to develop severe liver disease, including hepatocellular carcinoma. Although the development of direct-acting antivirals offers cure for a large majority of patients, there are still a number of clinical challenges. These include DAA failure in a significant subset of patients, difficult-to-treat genotypes and limited access to therapy due to high costs. Moreover, recent data indicate that the risk for liver cancer persists in patients with advanced fibrosis. These challenges highlight the need for continued efforts towards novel therapeutic strategies for HCV. Over the past two decades, advances in HCV model systems have enabled a detailed understanding of HCV entry and its clinical impact. Many of the virus-host interactions involved in HCV entry have now been identified and explored as antiviral targets. Furthermore, viral entry is recognized as an important factor for graft reinfection and establishment of persistent infection. HCV entry inhibitors, therefore, offer promising opportunities to address the limitations of DAAs. Here, we summarize recent advances in the field of HCV entry and discuss perspectives towards the prevention and cure of HCV infection and virus-induced liver disease.

Recent advances in hepatocellular carcinoma therapy

“…Almost 2.5%of the chronic HCV cases leads to HCC and the underlying virus-associated mechanisms is complex comprising both the host and viral factors where host-virus interactions lead to robust T-cell immune response elicitation (Colpitts & Baumert, 2016; Farazi & DePinho, 2006). …”

“…As a result, early diagnosis is crucial for successful treatment. Computed tomography (CT), magnetic resonance imaging (MRI), ultrasound and dynamic multiphasic multi-detector-row CT (MDCT) are the standard HCC diagnostic methods (Bertino et al, 2014; Daoudaki & Fouzas, 2014). Based on the tumor size, serum albumin, bilirubin and α-fetoprotein (AFP) levels, HCC morphology, presence of portal vein thrombosis and ascites, various classifications are used in order to categorize the stage of the disease, particularly Okuda staging system (I-III), Cancer of Liver Italian Program (CLIP) score (0-6), Barcelona Clinic Liver Cancer (BCLC) (Table 1), American Association for the Study of the Liver Disease (AASLD), National Comprehensive Cancer Network (NCCN) and European Association for the Study of the Liver (EASL) are noteworthy (Bertino et al, 2014; Trojan et al, 2016).…”

The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control

“…An antibody against Claudin-1 can control HCV in human liver chimeric mice [205]. It is possible that these entry inhibitors will have a role in future HCV therapy [206].…”

Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

“…These independent studies identified several structurally related compounds as potent HCV cell entry inhibitors both in vitro and in vivo. HCV cell entry is a complex process that involves multiple entry factors, among which the scavenger receptor class B type 1 (SR-B1), the tetraspanin CD81, and the tight junction proteins claudin-1 (CLDN1) and occludin (OCLN) are absolutely required (8,9). HCV is taken up, through clathrinmediated endocytosis, into host cells (10,11), where the viral glycoproteins E1 and E2 coordinate viral membrane fusion in a process that is triggered by the low pH in endosomes (12) (Fig.…”