Hepatitis C Virus: Strategies to Evade Antiviral Responses

Nandan S Gokhale; Christine Vazquez; Stacy M Horner

Disclosures

Future Virology. 2014;9(12):1061-1075. 

In This Article

Abstract and Introduction

Abstract

Hepatitis C virus (HCV) causes chronic liver disease and poses a major clinical and economic burden worldwide. HCV is an RNA virus that is sensed as nonself in the infected liver by host pattern recognition receptors, triggering downstream signaling to interferons (IFNs). The type III IFNs play an important role in immunity to HCV, and human genetic variation in their gene loci is associated with differential HCV infection outcomes. HCV evades host antiviral innate immune responses to mediate a persistent infection in the liver. This review focuses on anti-HCV innate immune sensing, signaling and effectors and the processes and proteins used by HCV to evade and regulate host innate immunity.

Introduction

HCV affects up to 2% of the world's population, with an estimated 130–170 million infected people worldwide, at the rate of 3–4 million new infections per year.[1,2] HCV is a blood-borne pathogen that is primarily transmitted through exposure to contaminated blood and often through intravenous drug usage. HCV can establish a chronic infection within hepatocytes of the liver, leading to liver cirrhosis and hepatocellular carcinoma. The liver disease caused by HCV leads to over 350,000 deaths per year globally.[1] Previously, hepatitis C patients were treated with pegylated IFN-α in conjunction with ribavirin, a therapy that produced an effective virological response against HCV genotype 1 in only about half of those treated.[3] In recent years, there have been major advances in HCV therapies, with several direct acting antivirals available on the market or finishing testing in clinical trials.[4,5] The RNA-dependent RNA polymerase inhibitor Sofusbuvir, taken with ribavirin, has been approved for use in patients infected with HCV genotypes 2 and 3.[5] Although this newly developed therapy is incredibly effective, it comes with a prohibitive cost of treatment, and viral resistance will likely emerge.[4,5] Furthermore, the lack of an effective vaccine for HCV ensures hepatitis C will remain a significant global health issue. This fact is further compounded by the comorbidity of HCV and HIV, which can share a common route of transmission in intravenous drug users.[6]

HCV, a member of the Flaviviridaefamily, is a single-stranded, positive-sense RNA virus. Upon infection of hepatocytes by HCV, the viral genome is released into the cytoplasm and gets translated into a single polyprotein that is processed by host and viral proteases into the structural and nonstructural proteins of the virus.[7] The viral genome is replicated through the orchestrated actions of the nonstructural HCV proteins in association with host intracellular membranes. During its life cycle, HCV is sensed by the host innate immune system by proteins called pattern recognition receptors (PRRs) that detect specific features within HCV to activate the antiviral innate immune response. A robust response by both the innate and adaptive arms of the immune system is required for effective immune clearance of HCV.[8] However, in spite of an activated immune response, HCV establishes a chronic infection in approximately 70–80% of infected patients.[2] The complex host–pathogen interactions that determine the divergent outcomes of HCV infection, as well as responses to therapy, are not yet fully understood, though it is known that human genetic variation, for instance at the locus of the genes encoding the type III interferons (IFNs), IFN-λ3 and IFN-λ4, is a critical factor that determines both natural and treatment-induced outcomes.[9,10] It is therefore imperative that we gain a greater insight into the immune responses to HCV and the strategies used by the virus to evade these responses in order to identify the key features of protective immunity to HCV.

In this review, we highlight recent advances in our understanding of the innate immune response to HCV. We will focus on how infected cells detect HCV as nonself and signal to activate antiviral IFN systems. We will discuss how HCV can evade these cellular antiviral systems by modulating the function of innate immune proteins, including the signaling adaptor protein MAVS. Furthermore, we will describe recent advances in how type III IFNs are activated and regulated during HCV infection, as well as the mechanisms by which antiviral effector proteins may restrict HCV infection. Taken together, this review will outline the major interactions at the interface of the host and HCV that likely contribute to the diverse outcomes of hepatitis C infection.

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