Impact of host and virus genome variability on HCV replication and response to interferon
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
References (76)
- et al.
Global epidemiology of hepatitis C virus infection
Lancet Infect Dis
(2005) Evolving epidemiology of hepatitis C virus
Clin Microbiol Infect: Off Publ Eur Soc Clin Microbiol Infect Dis
(2011)- et al.
Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy
Science
(1998) - et al.
Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region
J Clin Investig
(1995) - et al.
Hepatitis C virus non-structural 5A abrogates signal transducer and activator of transcription-1 nuclear translocation induced by IFN-alpha through dephosphorylation
World J Gastroenterol: WJG
(2007) - et al.
SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C
J Gastroenterol
(2005) - et al.
A polymorphism in MAPKAPK3 affects response to interferon therapy for chronic hepatitis C
Gastroenterology
(2009) - et al.
The dinucleotide microsatellite polymorphism of the IFNAR1 gene promoter correlates with responsiveness of hepatitis C patients to interferon
Hepatol Res: Off J Jpn Soc Hepatol
(2003) - et al.
Associations between the human MHC and sustained virologic response in the treatment of chronic hepatitis C virus infection
Genes Immun
(2008) - et al.
Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response
Hepatology
(2007)
A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus
Nat Genet
Factors that predict response of patients with hepatitis C virus infection to boceprevir
Gastroenterology
An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases
Hepatology
Epidemiology of viral hepatitis and hepatocellular carcinoma
Gastroenterology
Current and future therapies for hepatitis C virus infection
N Engl J Med
The natural history of hepatitis C virus infection: host, viral, and environmental factors
JAMA: J Am Med Assoc
Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group
N Engl J Med
Telaprevir for previously untreated chronic hepatitis C virus infection
N Engl J Med
Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial
Lancet
Rates of evolutionary change in viruses: patterns and determinants
Nat Rev Genet
New insights into the HCV quasispecies and compartmentalization
Semin Liver Dis
The origin of hepatitis C virus genotypes
J Gen Virol
Hepatitis C pharmacogenetics: state of the art in 2010
Hepatology
Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets
Proc Natl Acad Sci U S A
Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein
J Gen Virol
HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy
Gut
Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin
Hepatology
Mutations in the core and NS5A region of hepatitis C virus genotype 1b and correlation with response to pegylated-interferon-alpha 2b and ribavirin combination therapy
J Viral Hepat
Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy
Intervirology
NS5A sequence heterogeneity of hepatitis C virus genotype 4a predicts clinical outcome of pegylated-interferon-ribavirin therapy in Egyptian patients
J Clin Microbiol
Amino acid substitutions of hepatitis C virus core protein are not associated with intracellular antiviral response to interferon-alpha in vitro
Liver Int: Off J Int Assoc Study Liver
Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91
J Virol
IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3
FASEB J: Off Publ Fed Am Soc Exp Biol
Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs
J Med Virol
Repression of interferon regulatory factor 1 by hepatitis C virus core protein results in inhibition of antiviral and immunomodulatory genes
J Virol
Impairment of interferon regulatory factor-3 activation by hepatitis C virus core protein basic amino acid region 1
Biochem Biophys Res Commun
Hepatitis C virus NS5A: tales of a promiscuous protein
J Gen Virol
Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection
N Engl J Med
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