Hepatitis C Virus: Evading the Intracellular Innate Immunity

Abstract

Hepatitis C virus (HCV) infections constitute a major public health problem and are the main cause of chronic hepatitis and liver disease worldwide. The existing drugs, while effective, are expensive and associated with undesirable secondary effects. There is, hence, an urgent need to develop novel therapeutics, as well as an effective vaccine to prevent HCV infection. Understanding the interplay between HCV and the host cells will certainly contribute to better comprehend disease progression and may unravel possible new cellular targets for the development of novel antiviral therapeutics. Here, we review and discuss the interplay between HCV and the host cell innate immunity. We focus on the different cellular pathways that respond to, and counteract, HCV infection and highlight the evasion strategies developed by the virus to escape this intracellular response.

Keywords: antiviral response; antiviral signaling; hepatitis C virus; immune evasion; intracellular innate immunity.

Figure 1

Schematic representation of the hepatitis C virus (HCV) polyprotein referring to the individual proteins and their relevance for the HCV life cycle. The stars indicate cleavage sites of auto-proteases—blue star: NS2-3; red star: NS3-4A. N-terminal processing is accomplished by host proteases.

Figure 2

Hepatitis C virus (HCV) sensing by the intracellular innate immunity throughout the virus life cycle. Upon attachment to cellular receptors, HCV is internalized by endocytosis (1). Uncoating is then triggered and the viral genome is released into the cytoplasm (2). At the endoplasmic reticulum (ER) surface, viral RNA is translated (3), producing a polyprotein that it is co- and post-translationally processed into 10 viral proteins. Viral proteins’ expression induces the formation of a membranous web, which is essential for viral replication (4). HCV hijacks the lipid transport machinery for assembly (5) and uses the endosomal secretory pathway to be transported to the plasma membrane (6), where virion release occurs (7). The cytosolic sensors retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated protein 5 (MDA5) and protein kinase R (PKR) together with the membrane pattern recognition receptor toll-like receptor 3 (TLR3) recognize viral RNA inducing the downstream activation of interferons (IFNs) and proinflammatory cytokines’ production.3. Activation of the Intracellular Innate Immunity by HCV.

Figure 3

Evasion of the intracellular innate immunity response by hepatitis C virus (HCV) proteins. HCV NS3-4A, E2, NS5A, NS4B, p7, and core target several steps of the pattern recognition receptors (PRRs) signaling involved in HCV sensing, downregulating the expression of interferons (IFNs), proinflammatory cytokines and IFN-stimulated genes (ISGs), and consequently inhibiting the intracellular antiviral response.