Impact of host and virus genome variability on HCV replication and response to interferon

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Highlights

  • •

    Viral genome variants in Core and NS5A determine treatment outcome.

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    Host polymorphisms impact response to IFN treatment.

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    Newly discovered IFNL4 yields new possibility for HCV treatment.

Since the discovery of hepatitis C virus (HCV), treatment has proven difficult and the regimen of pegylated interferon-α and ribavirin is only effective for half of patients. Evidence suggests that host and viral genome variations play a role in either viral clearance or persistence. Powerful genomic technologies have made it possible to study genome-wide associations with treatment response, which yielded critical genetic polymorphisms that predict treatment response. This has important implications for treatment of HCV infection and opened the door to the possibility of genetic marker-guided treatment (personalized medicine). This review will focus on the recent advances in understanding host and viral genetic variations with regards to treatment and the importance for future therapeutic intervention

Introduction

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma [1] and new estimates suggest a global prevalence of 2.35%, affecting approximately 160 million individuals [2]. Up to 80% of acutely infected individuals will develop chronic infection and as many as 5% eventually progress to liver cancer [3]. Treatment of HCV infection with pegylated interferon-α and ribavirin (pegIFN-α/RBV) is successful in only 50% of patients [4]. Additionally, ethnic differences in HCV clearance and response to treatment are quite striking suggesting genetic factors play a vital role [5, 6]. New direct-acting antivirals (DAAs) have been introduced to the standard regimen and can increase the success to approximately 70% but may also lead to more adverse side effects [4, 7•, 8•].

HCV is an enveloped single-stranded RNA virus that targets hepatocytes in the liver. The HCV genomic RNA encodes for a large (∼3000 amino acids) polyprotein, which is cleaved into structural and nonstructural proteins by host and viral proteases. Like other RNA viruses, HCV replication is error-prone and has a high mutation rate. In addition to mutation, HCV infection produces a large population of new virions each day (1012–13) because of a large reservoir of infected hepatocytes [9]. Thus, viral genetic diversity can play an important role in viral persistence and treatment response, although the precise determinants are still under investigation.

In addition to viral genome variation, the host genomic variation is closely linked to success or failure during treatment. For this review we will focus on the identification of polymorphisms in the interferon lambda 3 (IFNL3, also known as IL28B) gene that are important for viral clearance during treatment. We will also discuss the implications of these findings for the future of DAA-based HCV treatment.

Section snippets

Viral genetic diversity and treatment response

The HCV RNA-dependent RNA polymerase NS5B lacks a 3′ to 5′ exonuclease, which is vital for proofreading activity. Thus the low fidelity of this enzyme yields a high degree of genetic variations and the estimated mutation rate for HCV is on the order of 10−4 to 10−5 substitutions per nucleotide copied [10]. Thus, HCV exists in vivo as a quasispecies, which is a dynamic distribution of nonidentical but closely related genomes [11]. This has contributed to the large genetic diversity observed

Core

The HCV core is an RNA-binding protein that forms the nucleocapsid of the virus. Core is important for viral assembly and is closely associated with lipid droplets [14, 15]. Specific polymorphisms in the core protein (amino acids 70 and 91) are associated with better response to treatment of genotype 1 [16, 17, 18, 19]. However, these same amino acid substitutions from genotype 4 infected patients did not correlate with treatment response [20]. A majority of the published data is from Japanese

NS5A

NS5A is a multifunctional phosphoprotein that is required for several stages of the virus life cycle [27]. Early studies suggested that variations or mutations in the C-terminal region of NS5A (amino acids 2209–2248), which was later designated as the interferon sensitivity-determining region (ISDR), were associated with better response to pegIFN-α/RBV [28]. Studies in Japanese patients confirmed that greater than four mutations within the ISDR correlated with sustained virological response

Discovery of IFNL3 (IL28B) polymorphism

Previously observed differences in the HCV clearance and response to treatment among different ethnic groups had long suggested that host genetic factors might play an important role. Initial studies examined candidate genes to identify differences or single nucleotide polymorphisms (SNPs) between two populations. A SNP is base-pair variant within the genome that has a frequency greater than 1% [42]. Several SNPs were identified in genes that are involved in the innate defense against HCV

Mechanism of IFNL3 SNPs in HCV treatment and clearance

Despite the dramatic effects the IFNL3 polymorphisms exert on treatment and clearance of HCV the precise mechanisms leading to this outcome are still unclear. It is well known that IFN-λ induces the expression of a multitude of ISGs that establish an antiviral state within effected cells. It is logical to hypothesize that the unfavorable genotypes exhibit a weak or attenuated ISG induction. However, it was demonstrated that hepatic expression of ISGs was markedly higher in patients who did not

IFNL3 polymorphisms and triple drug therapy

The identification of IFNL3 genotype was an important advance in understanding the varied response during pegIFN-α/RBV treatment. However, new direct acting antivirals (DAAs) were approved for treatment in early 2011 and it is logical to question the importance of IFNL3 in new treatment regimens. Two first-generation protease inhibitors, boceprevir and telaprevir, are used in combination with pegIFN-α/RBV as the standard treatment for HCV [4, 71]. Currently, the amount of data available to

Conclusion

HCV is a dynamic and exciting field of study. This relatively small virus has evolved innumerable ways to persist and establish a chronic infection within the liver. Viral genetic diversity has created a complex pathogen that is very difficult to treat and can actively subvert innate immunity. Additionally, we now understand how key genetic determinants within the host can have powerful effects on treatment and clearance of HCV. Expanding this research may yield novel aspects about immunity and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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