Activation and Evasion of Antiviral Innate Immunity by Hepatitis C Virus

doi:10.1016/j.jmb.2013.10.032

Journal of Molecular Biology

Volume 426, Issue 6, 20 March 2014, Pages 1198-1209

https://doi.org/10.1016/j.jmb.2013.10.032 Get rights and content

Highlights

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Sensing of HCV by pattern recognition receptors activates antiviral immunity.
•
The HCV NS3/4A protease cleaves and inactivates innate immune signaling proteins.
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Viral and host factors, including host IFNL3 genotype, affect anti-HCV responses.

Abstract

Hepatitis C virus (HCV) chronically infects 130–170 million people worldwide and is a major public health burden. HCV is an RNA virus that infects hepatocytes within liver, and this infection is sensed as non-self by the intracellular innate immune response to program antiviral immunity to HCV. HCV encodes several strategies to evade this antiviral response, and this evasion of innate immunity plays a key role in determining viral persistence. This review discusses the molecular mechanisms of how the intracellular innate immune system detects HCV infection, including how HCV pathogen-associated molecular patterns are generated during infection and where they are recognized as foreign by the innate immune system. Further, this review highlights the key innate immune evasion strategies used by HCV to establish persistent infection within the liver, as well as how host genotype influences the outcome of HCV infection. Understanding these HCV–host interactions is key in understanding how to target HCV during infection and for the design of more effective HCV therapies at the immunological level.

Graphical Abstract

Introduction

Hepatitis C virus (HCV) is an RNA virus that chronically infects 130–170 million people worldwide, with 3–4 million new infections per year [1]. HCV infects hepatocytes within the liver, and persistent infection by HCV in the liver leads to varying stages of liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma [1]. Every year, more than 350,000 people die from HCV-related liver diseases. Until recently, the standard of care for HCV was treatment with pegylated interferon-α and ribavirin and this was only effective in about 50% of infected patients [2]. The efficacy of HCV therapy has increased dramatically in recent years with the advent of direct acting antivirals, including the newly developed HCV protease and polymerase inhibitors [3]. While treatment with these therapies can lead to a successful treatment outcome up to 70% of the time, these therapies often have significant side effects, are by and large genotype specific, and can cause viral resistance to emerge [4]. Currently, there is no vaccine for HCV [5].

The host defenses that initially sense HCV infection take place within an arm of the immune system termed the antiviral innate immune response. This immune response is triggered in a cell intrinsic manner when pattern recognition receptors (PRRs) within the infected cell sense the virus as non-self or foreign and trigger downstream signaling cascades that activate immunity. This antiviral response is the first line of defense against viral infection, and not only can it be directly antiviral by acting to suppress viral replication and spread to other cells but this innate immune response is also required for programming functional adaptive immune responses and therefore coordinates the entire host immune response to infection. The importance of innate immunity in control of viral infection is underscored by the fact that many viruses, including HCV, have evolved ways to inactivate various innate immune signaling factors [6].

Interestingly, approximately 20–30% of people who are infected with HCV clear the virus during the acute stage of infection, while 70–80% develop a chronic, life-long infection [1]. The mechanisms that underlie these differences are still not fully understood but likely reflect a complex interplay between the virus and the host at the level of the immune response. Therefore, a detailed understanding of what makes up an effective immune response to HCV and how HCV counteracts this immune response will be essential for developing new antiviral strategies, with the ultimate goal of reducing the disease burden of HCV, including preventing liver disease and cancer. This review will focus on recent advances in how HCV activates and then subsequently evades the antiviral innate immune response to establish a productive infection. In addition, this review will discuss how the host genetic background influences the antiviral response to HCV in both natural and treatment-induced clearance.

Section snippets

How Is HCV Sensed as Non-Self?

The innate immune response to RNA viruses is composed of three main classes of PRRs, termed the RIG-I (retinoic acid-inducible gene I)-like receptors (RLRs), the toll-like receptors (TLRs), and the Nod (nucleotide oligomerization domain)-like receptors (NLRs) [7]. These proteins sense specific features called pathogen-associated molecular patterns (PAMPs) within the viruses or present during viral infection. Following PAMP recognition, PRRs signal through various downstream molecules to

Immune Effectors of HCV

Innate immunity activates a signaling cascade that induces IFN and also hundreds of ISGs, many with direct antiviral properties that control virus replication and spread [106], [107]. One of the major therapies for HCV utilizes IFN-α, which can drive expression of ISGs, even in the infected patient [108]. As IFN-α-based therapies are effective at eliminating HCV in about half of those infected with the virus, ISGs likely have some direct antiviral activity toward HCV in the infected hepatocyte.

HCV Subversion of Innate Immune Surveillance Programs

Despite the fact that HCV is sensed by many different innate immune pathways, in about 80% of those infected, the immune response does not effectively clear the virus, resulting in a life-long chronic infection [121]. While there could be many factors that contribute to the ability of the virus establish chronic infection, one hypothesis is that HCV evasion of host innate immune signaling contributes to viral persistence and chronicity. HCV utilizes several mechanisms to evade innate immunity.

IFN Response to HCV

In spite of the fact that HCV has multiple strategies to antagonize innate immune signaling pathways, many patients infected with HCV display high hepatic ISG mRNA activation profiles within the liver [108], [141], [142], [143]. Further, hepatitis C patients that have induced expression of ISGs prior to therapy are the ones that most often do not respond to therapy. There are many questions that remain concerning these pre-therapy-induced ISGs, including how are these ISGs induced prior to

Conclusions

We now know that HCV is sensed as foreign or non-self by multiple arms of the innate immune response, and activation of all of these responses would be key to priming a functional adaptive response that would lead to eventual viral clearance. However, HCV antagonism of the innate immune response, both at the level of the IFN response and the IFN induction pathways, likely plays a key role in viral pathogenesis and ability of the virus to maintain a persistent, life-long infection in many who

Acknowledgments

I would like to thank Dr. Courtney Wilkins, Dr. Arjun Rustagi, and John Errett for helpful suggestions and critical reading of this manuscript.

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Journal of Molecular Biology

ReviewActivation and Evasion of Antiviral Innate Immunity by Hepatitis C Virus

Highlights

Abstract

Graphical Abstract

Introduction

Section snippets

How Is HCV Sensed as Non-Self?

Immune Effectors of HCV

HCV Subversion of Innate Immune Surveillance Programs

IFN Response to HCV

Conclusions

Acknowledgments

J Hepatol

Curr Opin Immunol

Curr Opin Virol

Antiviral Res

Trends Microbiol

Curr Opin Microbiol

Mol Ther

Mol Cell

Mol Cell

Structure

Cell Host Microbe

Cell

J Biol Chem

Cell

Cell

Cell Host Microbe

Immunity

Cell Reprogram

Gastroenterology

Cell Host Microbe

Cell Host Microbe

Virology

Antiviral Res

J Biol Chem

J Biol Chem

Gastroenterology

J Hepatol

J Hepatol

The global burden of hepatitis C

Liver Int

New therapies for hepatitis C virus infection

Clin Infect Dis

A new standard of care for the treatment of chronic HCV infection

Nat Rev Gastroenterol Hepatol

Current progress in development of hepatitis C virus vaccines

Nat Med

Viral evasion and subversion of pattern-recognition receptor signalling

Nat Rev Immunol

Nomenclature and numbering of the hepatitis C virus

Methods Mol Biol

Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and assignment Web resource

Hepatology

Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes

Semin Liver Dis

Replication of hepatitis C virus

Nat Rev Microbiol

Understanding the hepatitis C virus life cycle paves the way for highly effective therapies

Nat Med

Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2

Proc Natl Acad Sci USA

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Nat Immunol

RIGorous detection: exposing virus through RNA sensing

Science

Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5

J Exp Med

Hepatitis C virus reveals a novel early control in acute immune response

PLoS Pathog

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Proc Natl Acad Sci USA

Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I

J Virol

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Nature

Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities

J Virol

Uridine composition of the poly-U/UC tract of HCV RNA defines non-self recognition by RIG-I

Review
Activation and Evasion of Antiviral Innate Immunity by Hepatitis C Virus