Top
×
Hepatoma Res 2018;4:23.10.20517/2394-5079.2018.25© The Author(s) 2018.
Open AccessReview

Molecular targeting of antiviral drugs used against hepatitis C virus infection

See all authors and affiliations

1Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.

2Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India.

Correspondence Address: Prof. Mohammad Irshad, Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: drirshad54@yahoo.com

    Science Editor: Guang-Wen Cao | Copy Editor: Jun-Yao Li | Production Editor: Cai-Hong Wang
    ...

    © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

    Abstract

    Present study reports an update on the molecular interaction of antiviral drugs with viral and host cell components during hepatitis C virus (HCV) infection. In addition to the traditional therapeutic drug regimen, termed as standard of care, some recent drugs have been added in the existing regimen used for HCV infection. These drugs were categorized as direct-acting antivirals (DAAs) agents and “other agents”, with their efficacious impact in the control of HCV infection. They target both viral proteases and host cell receptor proteins/enzymes involved in HCV entry into the cell, replication, and assembly to check their propagation both in situ as well as in cell to cell transmission. Recent studies have reported a significant rise in sustained virological response after the use of these drugs both alone and in combination with pegylated interferon-α (PegIFN-α) plus ribavirin. Recently, DAAs have been reported to be highly effective in eradication of HCV infection, especially liver cirrhosis, reducing but not avoiding the occurrence of liver cancer. Some studies have demonstrated that the presence of resistant HCV variants, arising during viral replication, may be controlled by the new drug regimen. It is important to note here that all these drugs are influenced by viral as well as host factors including basic viral load, HCV genotypes, IFN action, interleukin 28B polymorphism and some liver and metabolic diseases, etc. This is an area with on-going investigations to explore more antiviral agents that may address new challenges in HCV therapy.

    Introduction

    Hepatitis C virus (HCV) infection is a known cause of serious liver diseases recorded worldwide. Majority of infections are asymptomatic and in about 80% of cases, the virus persists without the patient’s awareness. HCV infection causes both acute as well as chronic liver diseases including cirrhosis of liver and hepatocellular carcinoma. Globally, HCV infection affects nearly 180 million people[1] which account for 3% population of the world. Approximately 3 million new cases are added to this population every year[2,3]. A high proportion of HCV infected patients develop chronic liver diseases and nearly 20% of them progress to cirrhosis and about 10% to liver cancer[4,5] in later stage. The presence of HCV infection, though varies from region to region, has been noted throughout the world. Hepatitis B virus (HBV)-based prevention and control measures for viral hepatitis have achieved remarkable results, and hepatitis C has relatively little awareness. Efforts have been made to develop effective prophylactic and therapeutic measures for treatment of chronic HCV infection. There is a common belief now that HCV infection needs more attention even than human immunodeficiency virus (HIV) infection in terms of its early detection and timely remedies since both of them do not have any vaccine for prevention. Moreover, the disease burden caused by HCV is also more serious even than HIV. A high genomic variability in HCV has led to development of at least seven genotypes and many isotypes.

    HCV is an RNA virus with about 9.6 kb genome. This is a single stranded, enveloped virus with positive polarity and has been categorized under flaviviridae family. Its genome has a single ORF encoding for polypeptides of 3011 amino acids. The 5’UTR region has an internal ribosomal entry site (IRES) which is involved in HCV replication. Using host and viral proteases, HCV polyprotein is cleaved into three structural proteins (Core, E1 and E2) and seven non-structural proteins (P7, NS2, NS3, NS4A, NS4B, NS5A and NS5B)[6]. HCV-core forms viral nucleotide that has significant role in viral pathogenesis[7] and E1 and E2 proteins are involved in viral entry into the cell[8]. The P7, a 63-amino acid protein, helps in translocation of NS2 into endoplasmic reticulum and also in viral assembly and release of HCV virions[9,10]. The NS2 peptide is a transmembrane protein which plays role in viral replication. The NS3, on the contrary, is a protease and acts as ATPase/helicase[11,12]. Usually, HCV protease disrupts interferon (IFN) and toll-like receptor-3 (TLR-3) signaling pathways. The NS4A acts as a cofactor for NS3 protease, the NS4B is needed to recruit other viral proteins[13,14] and NS5A, a phosphoprotein, plays role in viral replication[15,16]. The last non-structural protein i.e. NS5B is an HCV RNA dependent RNA polymerase (RdRp) which also participates in RNA replication[17].

    The studies available in last few decades have elucidated the virus specific events in infected cells. In order to use these events as targets for chemotherapy, some antiviral agents were developed and used to treat HCV infection on a line similar to the one used for other viral infections. This targeting is aimed to suppress virus reproduction without an adverse effect on the host-cell. There are a number of virus specific processes within virus replicative cycle in an infected cell that may be targeted for chemotherapeutic intervention. The major target steps include virus entry into the cell, reverse transcription, viral DNA/RNA polymerization and the reactions involved in viral DNA/RNA synthesis etc. At present, a variety of agents including nucleosides and non-nucleosides entities have been developed which interact with virus targets and inhibit virus replication. In case of treating HCV infection, today a variety of agents are available for use. In addition to the virus-specific events, there are several host enzymes and processes that are closely associated with viral DNA, RNA or protein synthesis. These processes may also be the targets for antiviral agents.

    The recommended treatment for HCV infection includes a combination therapy with PegIFN and ribavirin[18]. However, recently several new regimens have been evolved for treatment of HCV infection. The drugs including direct-acting antiviral agents (DAAs) like boceprevir or telaprevir as protease inhibitors have provided a new promise to aim the HCV treatment. This therapy improves sustained virological response (SVR) in patients infected with HCV genotype-1 by more than 70%. Moreover, it has an additional significance of little chances of development of drugs resistant variants[19-21]. Several other DAAs are in clinical trials today and have been evaluated for combination therapy[22]. The emerging new antivirals need a new trial for serious liver diseases, particularly, in those cases with poor response to current regimens[23,24].

    Present study gives an update on the availability and action of therapeutic agents targeting various steps of HCV viral life cycle and infected host cell processes that may be disrupted to check viral reproduction and underlying pathological reaction cascade. It also describes the comparative efficacies of different agents and the future of HCV- treatment under the use of these agents.

    Types of drugs

    In a common practice, the combination of pegylated interferon-α (PegIFN-α) and ribavirin, is used for the treatment of HCV infection[18]. The addition of DAAs, like boceprevir, ortelaprevir, in the drug regimen, has brought a new change in the status of HCV treatment. This regimen improves the SVR to a significant level even in genotype-1 infected patients[19]. IFN and ribavirin can cause patients with flu-like symptoms, cognitive dysfunction, thyroid dysfunction and other adverse reactions, leading to premature termination of treatment in some patients. However DAAs were found to develop drug resistant variants[20,21]. Subsequent studies introduced the next generation DAAs like simprevir and sofosbuvir, that were approved by FDA for treatment of HCV infection[21,25]. An interferon free drug regimen comprising ombitasvir, paritaprevir, ritonavir and dasabuvir has been approved for HCV genotype-1 infected patients. Now it is believed that the new drug combination may consist of interferon free regimen with high viral killing efficiency, short therapy time and less adverse effect. The development of drugs and their different combinations for an effective therapy against HCV is under investigation for last several years. Some new drugs developed and used in recent past are described in Table 1. These drugs are used both alone as well as in combination to other drugs. Based on their nature, action and host response, these drugs have been classified under different categories:

    Table 1

    Mechanism of drug action to control HCV infection

    Site of action (target)DrugsMechanism of action
    Viral entry
     AttachmentLectin cyanovirin-N, BA-LNC, Ficolin, Heparin and heparin-derived compounds, Heparanase, EGCG and its derivatives, Lactoferrin, A p7 ion channel-derived peptide H2-3Inhibits attachment factors reducing concentration of virions on cell surface
     Post-binding interactions with entry factors
      CD81Imidazole-based compounds, Anti-CD81 mAbs, Soluble CD81 LELInhibits viral binding with entry factors
      SRB1Serum amyloid A,
    Anti-SRB1 pAb and mAb, ITX5061
      CLDN1Anti-CLDN1 peptides,
    Anti-CLDN1 pAb and mAb
      EGFRErlotinib
      EphA2Dasatinib
      TfR1Anti-TfR1 mAbs, Ferristatin
      NPC1L1Anti-NPC1L1 mAbs, Ezetimibe
     Clathrin-mediated endocytosisChlorpromazine, ArbidolRestrict endocytosis of virions
     Fusion and uncoating
      Endosome acidificationConcanamycin A, Bafilomycin A Chloroquine, Ammonium chlorideReduces acidification of endosome required for membrane fusion between virus and host cell
      Lipid composition of virus or host cell
    Arbidol, Phenothiazines, RAFIs (aUY11), LJ001, SilymarinReduced fusion efficiency of HCV particles
     Unclear mechanismFerroquine, PS-ONs
     Natural compounds and small moleculesFlavonoids, Terpenoids, Tannic acid, Gallic acid, PF-429242Exact mechanism not elucidated
    Viral replication
    Interferon
    PegIFN-α, Human serum albumin IFN-α,
    PegIFN-λ-1a
    IFN-alpha declines HCV RNA level
     Viral proteinRibavirin (Nucleoside analogue)
    DAAs
    Mechanism unclear
      NS3/4ATelaprevir, Boceprevir, Faldaprevir, Simeprevir, Asunaprevir, Paritaprevir, Danoprevir, Grazoprevir, Vaniprevir, TMC435Inhibits NS3/4A proteases involved in viral replication
      NS5ADaclatasvir, Ledipasvir, Ombitasvir, Elbasvir, VelpatasvirInhibits binding of NS5A to viral RNA required for RNA replication and viral assembly of HCV
      NS5BSofosbuvir, Dasabuvir, Mericitabine BI207127, Lomibuvir/VX-222, SetrobuvirInhibits NS5B, RNA-dependent RNA polymerase inhibitor
      NS33-bromo-4-hydroxyl derivative 4,5,6,7 –tetrobromo benzotriazole (TBBT), 30-methylpiperidine-10-Yl QU663NS3 helicase inhibitor
    Protein kinase-2 inhibitor
    Helicase inhibits
    NS3 helicase inhibitor
      NS4BClemizoleInhibits HCV RNA replication by blocking binding of viral RNA to NS4B
     Host factors
      CyclophilinsCyclosporin AInhibit HCV replication
      miRNAMiravirsenReduces HCV replication
    Viral assembly
     Alpha-glucosidaseUT-231B (Immino sugar) and Celgosivir
    (MX-3253-a castano- spermine prodrug)
    Inhibits alpha glucosidase involved in HCV assembly
     DGAT-1 (Cellular factor) (Diacylglycerol
    O- acyltransferase-1)
    DGAT-1 inhibitorInhibits DGAT-1 needed for core protein localization around LDs
     DGAT-2 (Cellular factor) (Diacylglycerol O- acyltransferase-2)DGAT-2 inhibitorDGAT-2 involved in LD biogenesis
     VLDL biogenesisGrapefruit flavonoid naringeninInhibitor of VLDL secretion disturbing viral assembly

    Interferon

    PegIFN-α, a commonly used drug increases the SVR rate by causing a delay in renal clearance. Human albumin-IFN-α (Albinterferon) is a fusion protein. This protein is used for the treatment of HCV infection. Different reports have shown that the SVR rate arising from the use of Albinterferon and Ribavirin was nearly the same as noted with use of the SOC treatments[26,27]. Similarly, IFN-λ which is a class-III interferon, is also used for the treatment of HCV infection. The receptors of IFN-λ are mainly present in the liver and therefore very minimal extrahepatic adverse effects were recorded with the use of IFN-λ in comparison to IFN-α[28].

    Direct acting antiviral agents

    This is the class of drugs acting against viral and host proteins involved in HCV life cycle. The major inhibitors of NS3 viral protein are telaprevir and boceprevir. Telaprevir was approved and recommended for use with PegIFN-α and ribavirin in genotype-1 patients. This was classified as triple therapy. Since telaprevir treatment is reported to be effective against the resistant mutants in the short term duration, it was decided to use it for long-term and subsequently approved for the treatment[29]. It is important to note here that the long term use of these drugs often leads to drug resistance including T54A/S, R155K/T, V36A/M, V55A, and A156/S/T/V, etc. Simeprevir is another NS3 protease inhibitor classified as second generation drug. This drug is a reversible inhibitor of NS3/4A protease[30]. Danoprevir and faldaprevir are also second-generation HCV NS3/4A protease inhibitors and used in patients infected HCV genotype-1. In addition to these drugs, there are various other NS3 protease inhibitors like Vaniprevir (MK-7009), Narlaprevir (SCH 900518), Asunaprevir (BMS 650032), VX 985, and MK-5172 which are used for treatment of HCV infection. There is every possibility that these drugs may be approved for therapeutic use against HCV infection[29].

    Daclatasvir (BMS) 790052 was found to inhibit NS5A, a protein involved in HCV replication and therefore used as a drug for control of HCV infection. This particular drug has a broad genotype antiviral activity. In addition, other NS5A inhibitors include Ledipasvir (GS-5885), ABT 267, IDX791, and ACH-2928 etc. NS5B is a RNA-dependent RNA polymerase (RdRp) involved in HCV replication. This NS5B enzyme activity is inhibited by two categories of inhibitors that are nucleoside/nucleotide derivative inhibitors (NIs) and non-nucleotide inhibitors (NNIs). It has been found that NIs have a similar effect for different HCV genotypes and also show low incidence of resistant genes. Sofosbuvir, a NIs, has been used in cases of HCV infection caused by non-genotype-1 HCV[31,32]. However, DAAs are well tolerated and adverse reactions are significantly lower than IFN, but there are still a few cases of adverse reactions and reactivation of HBV during DAAs anti-HCV treatment[31].

    Cyclosporine and miravirsen

    Cyclophilins including cyclophilins A, B, and C are involved in HCV replication. An immunosuppressive compound cyclosporine A is involved in the inhibition of HCV RNA replication by interfering with cyclophilins A functions. Alisporivir (Debio-025) which is a derivative of cyclosporine A acts as antiviral agent against many HCV genotypes. The antiviral effect of cyclophilin inhibitors is increased when used in combination with PegIFN-α. Thus, in addition to many other benefits, these agents may be used as effective antiviral agents[33,34]. Miravirsen is another drug that targets miRNA-122. It inhibits several HCV genotypes in vitro. Its effect lasts long simultaneous with non-appearance of resistant mutations.

    Other antiviral agents

    In addition to antiviral agents described above, vitamin B12 was also reported to act as an inhibitor of HCV replication. The use of vitamin B12 with SOC drugs raised the SVR rate to the level higher than the rate noted in patients treated with SOC alone[35]. Recently, it has been observed that vitamin D also acts against HCV in vitro. The SVR rate of patients infected with HCV genotype-1 or 2/3 is improved once vitamin D is added to PegIFN-α and ribavirin therapy[36,37]. A comparison of study using PegIFN-α and RBV with supplement of L-carnitine group vs. the PegIFN-α plus RBV group has shown an increase in SVR rate[38]. This substantiates that L-carnitine may be useful for the treatment of HCV infection.

    Mechanism of drug-action

    Targets of drugs

    The basic aim of designing the drugs against HCV infection is to develop agents that can check the entry of virus into cells, blocks its replication and disrupts the viral assembly inside the cell. As such, drugs do not kill the virus or its components but prevent their formation and reproduction. In case of HCV infection, attempts were made to develop drugs that can check viral entry and replication process. Since the discovery of HCV, a number of experimental studies were conducted which reported detailed analysis of HCV life cycle and its interaction with human host. These studies revealed several targets for therapeutic intervention in HCV infection. Recent improvements in the SOC therapy have raised the hope that HCV infection can be managed with adequate medical intervention. However, the current treatment is not effective for all seven genotypes. The basic aim for HCV therapy is to achieve high SVR using traditional drugs in combination with direct acting antivirals (DAAs), without any chance of escape mutations.

    HCV entry as target

    The drugs inhibiting HCV entry into cells target receptors and enzymes helping in viral entry process. These entry inhibitors have prophylactic properties and show synergistic effect when combined with other agents[39]. Circulating virions bind with glycosaminoglycans (GAGs) and LDLA[40]. The lectin cyanovirin-N (CV-N) impairs viral binding by its interaction with E1/E2 HCV proteins to check entry[41]. Similarly, L-ficolin proteins can neutralize HCV particles through their binding to E1/E2 proteins[42]. Epigallocatechins gallate (ECGC), a natural polyphenol compound and abundant in green tea extract regulate lipid metabolism impairs HCV binding to host cell by interfering with HCV E1/E2 function and also block cell-to-cell transmission in vitro[43-45]. This is the reason that green tea is considered as an effector against HCV infection. Lactoferin, present in milk, also blocks HCV attachment[46]. Like E1/E2, the P7 protein also inhibits HCV entry by directly effecting virus binding to cell surface and interfering with host-virus interaction[47].

    After attachment of virus with cell surface, its entry requires different host factors like CD81, SRB1, CLDN1 and OCCDN1, jfRI, EGFR, EphA2 and NPC1-L1, etc. CD81 interacts with HCV E2 helping HCV infection. Specific NTCD81 monoclonal antibodies like JS-81 or KO4 counteract HCV E2-CD81 interactions and interfere with HCV entry during post binding process[48-53]. SRB1 proteins, related to lipid metabolism, also affect HCV entry to host cells[54]. Serum amyloid A, an acute phase protein and produced by liver, inhibits HCV entry[55-57]. Similarly, ITX5061, a small molecule, also blocks uptake of HCV and functions synergistically with DAAs, thus giving a promise for future use. CLDNs and OCLNs form complex with CD81 and contribute to efficient HCV internalizations. Since CLDN1 is highly expressed in hepatocytes, it may be a potential target for antiviral agents. Antibodies vs. CLDN1 show inhibitory effect on HCV infection[58-60]. OCLN is also a main entry factor for HCV. Recently, it has been found that mi R-122 can decrease HCV entry by inhibiting OCLN. The EGFR and EphA2, the receptor tyrosine kinases (RTKs), act as cofactors for HCV entry[61]. These are expressed in liver and inhibited by anticancer drugs like Erlotinib and Desatinib. These drugs impair HCV cell-entry. RTKs interfere with CD81-CLDN1 complex association and block cell to cell transmission of HCV[61]. However, their efficiency needs further authentication. After interaction with various receptors, HCV particles are internalized through clatherin-mediated endocytosis[62]. CD81-CLDN1 complex facilitates virus entry and fusion simultaneously[58]. The compound chloropromazine interferes with clatherin, thus impairing HCV endocytosis[63]. Arbidol, used as an anti-influenza drug, impairs clatherin mediated endocytosis of HCV[64]. The fusion of virus membrane to host cell is followed by viral replication inside the cell. The indole derivative arbidol also inhibits HCV membrane fusion[65]. Silymarin is a mixture of several flavonolignans and flavonoid taxifolines and inhibits fusion as done by arbidol[66]. Other fusion inhibitors include feroquine and aclorocquin, etc.

    HCV replication as target

    The HCV replication cycle presents another important target for antiviral therapy. The successful use of protease inhibitors for the treatment of HIV infections prompted researchers to focus on the HCV associated enzymes including NS3-4A protease and NS5B polymerase, etc.[67,68]. The HCV RdRp also became an attractive drug target. Finally, inhibitors targeting NS5A have also been developed. Simultaneous with viral proteins, several host cellular components were also used as targets while developing drugs against them.

    NS3 is a component of HCV encoded polyprotein which together with NS4A, constitutes the protease NS3-4A. Its carboxy-terminal region shows RNA helicase and NTPase activity[69]. Both these proteases are essential for HCV replication and have been pursued as drug targets. Since NS3-4A binds with its substrate by weak interactions, this restricts the development of drugs targeting NS3-4A. However, later studies could be successful in developing certain DAAs targeting NS3-4A[70]. These drugs were put under three different categories on the ground of their properties and action[71]. The DAAs in category I include linear peptidomimetics that bind proteases enzymes through covalent bonds. For example, telaprevir and boceprevir, the drugs of class I bind to the active-site Ser (Serine) forming a covalent enzyme - inhibitor adduct. This not only shows antiviral activity but also uses strong forces to bind the target site. DAAs under category II and III are NS3-4A specific drugs. These are linear peptidomimetics or macrocyclic inhibitors and do not bind with their target by covalent bonds. It has been reported that these drugs do not target all HCV genotypes. These NS3-4A inhibitors are two macrocycles MK-5172[72] and ACH-2684[73].

    The NS5A replicase is the most enigmatic HCV protein. On the basis of molecular masses, their predominant forms are p56 and p58, respectively[74]. The phosphorylation in NS5A replicase is reported to be mediated by different kinases[75,76]. It has several sites identified as targets in the central and c-terminal part of NS5A and LCS1 region. The RdRp-NS5B is another enzyme regulating viral RNA synthesis. Several studies have demonstrated the candidate NS5B inhibitors which are nucleoside and nucleotide inhibitors (NIs) in nature and bind at active site of the enzyme. The non-nucleoside inhibitors (NNIs) bind at allosteric sites to bring conformational changes and inhibit polymerase activity[67,68,71]. These NIs have been reported to be effective against several HCV genotypes.

    HCV replication is a complex process involving many other viral proteins simultaneous with NS3-4A, NS5A and NS5B. These proteins have been pursued as drug targets. Moreover, there are some non-enzymatic proteins which also make a suitable intervention point. Although the exact function of NS4B is not very clear, it has been found as a good drug target[77]. NS4B also plays an important role in HCV RNA replication by forming membranous replication complexes. It has been observed that the C-terminal portion of NS4B is needed for functional HCV replication complexes[78]. Clemizole has been found as a potent inhibitor of HCV RNA replication. This agent blocks the binding of viral RNA to NS4B[79].

    Apart from viral proteins, some host cell factors also emerged as promising targets for antiviral therapy. Among host factors contributing to the viral replication cycle, we describe here two main factors that have been studied in detail, which are cyclophilins and miR-122. Cyclophilins A (CYPA) is the primary host factor and targeted by immunosuppressive drug cyclosporin A (CsA)[80,81] which inhibits HCV replication in cell culture[82]. The CYPA-CsA complex also inhibits calcineurin, involved in activation of T cells. Some CYPA antagonists have been developed. These compounds are Alisporivir, NIM811 and SCY635. miRNA-122 is another important host factor that was targeted for the treatment of chronic HCV infection. miRNA-122 stimulates HCV replication by stabilizing HCV RNA[83,84], translates of the viral genome[85] and enhances RNA replication[83]. Naturally, targeting miRNA-122 by antagonist disrupts HCV replication in vitro and in vivo[86,87] and therefore becomes an effective target of therapy. miRNA-122 also shows the important role in hepatocyte lipid homeostasis and it may be taken into account when considering the therapeutic use of miRNA-122 antagonists.

    HCV assembly as target

    The experimental studies indicated that antiviral molecules act at different steps of HCV lifecycle. Also many cellular factors act as candidate targets. The inhibition of α-glucosidases disrupts HCV assembly[88,89]. The α-glucosidase inhibitors including UT-231B and Celgosivir (MX-3253-a castano-spermine prodrug), were used as assembly antagonists[90,91]. Identification of diacylglycerol O-acyltransferase-1 (DGAT1), the factor needed for core protein localization around LDs, indicates that DGAT1 may be a target for therapeutic intervention[92]. Although diacylglycerol O-acyltransferase-2 (DGAT2) is also involved in LD biogenesis[93], HCV targets only DGAT1. Furthermore, DGAT2-generated LDs form normally in DGAT1 inhibitor treated cells. This shows a limited effect of DGAT1 inhibitors on the cellular functions[92].

    Effect of viral and host components on drug action

    Basline viral load

    When baseline viral load is less than 400,000-800,000 IU/mL, the course of treatment may be reduced to 24 weeks in genotype-1/4 patients and to 12-16 weeks in gneotype-2/3 patients. Many studies have shown that low viral load (HCV-RNA, 600,000-800,000 IU/mL is a good predictor of SVR[94-96]. An increase in viral load decreases SVR rate.

    Viral genotypes

    HCV has a total of seven genotypes with more than 50 subtypes and several quasispecies. Genotypes play very important roles in deciding the host response to anti- viral treatment. Patients infected with genotype-1, -4, -5, -6 respond worse than those with genotype-2/3 infection. Although, it is not fully established, it is believed that DAAs have better effect on non-responder genotypes like genotype-1. Using sofosbuvir drug it has been altered that when it is combined with the SOC regimen, there is a good impact on SVR, both in genotype-1 and genotype-2/3 patients[97,98].

    Interferon action

    Interferons are involved in host natural immune response against various pathogens including HCV[99]. Interferon binds with receptors on the target cells and activates signaling pathways like JAK-STAT pathway. This upregulates IFN-stimulated genes (ISGs) with expression of several types of antiviral effector protein[100-102]. This has been a basis of using IFN-α as an antiviral agent in chronic HCV infection[103]. However, some studies have demonstrated that IFN-α based treatment of HCV infection is influenced by several factors including viral as well as host factors. Viral load and HCV genotypes were found to be important factors influencing IFN-therapy. HCV genotype-1 responded poorly to IFN therapy achieving SVR to near about 50% in comparison to HCV genotype-2 and -3 where SVR reached up to 85%[104]. It has been found that many HCV proteins interfere in the antiviral action of IFN-α[105]. Subsequently, it was noted that various HCV proteins including Core, E2, NS3/4A, NS5A/5B, antagonize antiviral effect of IFN-α. It may be illustrated more specifically in reference to individual HCV viral proteins. For example, HCV core induces expression of Suppressor of cytokine signaling-3 and -1 (SOCS-3 and SOCS-1), which antagonize IFN-α action by blocking JAK/STAT-pathway and ISGs expression[106,107]. HCV core also inhibits IFN induced phosphorylation and nuclear translocation of STAT-1. Binding of HCV core to STAT-1 decreases its phosphorylation and ISGs transcription[108,109]. Another important structural protein HCV E2 was also found inactivating IFN-α through inhibition of PKR[110]. This effect of E2 was detected prominently in patients infected with HCV-1 isolate. HCV genotype-2 and -3 could not show the same effect[110]. Of the nonstructural proteins, HCV NS3/4A was found to disrupt the IFN induction pathway. HCV NS3/4A protease cleaves various proteins including antiviral signaling proteins (MAVs)[111,112], TIR domain containing adaptor inducing IFN-α (TRIF)[113] and adapter protein of RIG-1 TLR-3 signaling pathways etc. This cleavage disrupts not only innate immune response but also IFN-induction pathway, ultimately resulting in down regulation of the transcription of IFN-alpha inducible genes[114,115]. In addition, HCV NS4B and NS5A were also found to inhibit protective action of IFN-α. NS4B reduces IFN-α induced phosphorylation of STAT-1 and expression of IFN receptors. On the other hand NS5A binds and inactivates PKR[116-118]. Several studies have shown inhibitory effect of NS5A on IFN induced JAK-STAT signaling pathway[119-121]. NS5A usually blocks IFN-1 induced STAT-1 phosphorylation and its nuclear translocation resulting in downregulation of ISGs induced expression.

    IL28B polymorphism

    Single nucleotide polymorphism (SNP) in IL28B gene present on chromosome 9 has an impact on HCV treatment response. The SVR rate of SOC in HCV patients carrying CC genotypes was 2-3 times higher as compared to the one with its clearance. There is high frequency of CC genotypes[122] in comparison to European and African. IL28B polymorphism is the best predictor of treatment response, better even than viral load, liver fibrosis, glucose level etc. EASL guidelines showed that IL28B polymorphism can be used to give a predictive value. Thus IL28B gene has a better predictive value in comparison to SOC and DAAs.

    Hepatic steatosis

    Patients with hepatic steatosis usually do not respond well to HCV infection treatment. The presence of steatosis does not allow the EVR or SVR to attain in genotype-1 infected patients when treated with SOC. Similarly, steatosis affects negatively in patients infected with other genotypes. It causes relapse after discontinuation of treatment in patients with genotype-3. This all indicates that pathogenesis of steatosis differs in different genotypes and influences the treatment. In addition to all above factors influencing the treatment response, other conditions like age, insulin resistance, and metabolic syndrome etc. also have negative impacts on treatment.

    Virological response to therapy

    The therapy of HCV infection is basically aimed to eradicate the virus and prevent the ensuing disease complications. The success of therapy is monitored by SVR rate which is defined as the absence of the HCV RNA in serum post 24 weeks of stoppage of treatment[123]. The value of SVR indicated not only eradication of virion from circulation but also correlates with symptoms[124-127]. The combination of PegIFN and ribavirin has been the SOC for all patients infected with HCV irrespective of viral genotypes[123]. This regimen produces SVR to 70%-80% in patients with HCV genotype-2 or -3 infection. However, SVR reached only 45%-70% in patients infected with other genotypes[123]. In recent trials of boceprevir and telaprevir in patients with cirrhosis it was noted that SVR was low in comparison to that in non-cirrhotic patients.

    Drug resistance

    HCV is a highly variable virus with a large viral population and numerous quasispecies turnover in an infected individual. Its life cycle remains confined to the cytoplasm in cell with little possibility of its genome integration with host genome. Treatment of chronic HCV infection is based on the combination of PegIFN-α and ribavirin. The use of DAAs against HCV demonstrates that these agents may give rise to drug resistant viral species. These viral variants have different amino acid composition on target sites and so, are less susceptible to drug action[128]. In fact, the variants preexist before treatment, possibly arising from error prone activities of HCV-RNA dependent RNA polymerase (RdRp)[129] and rarely detected by current techniques. Drug exposure inhibits replication of the dominant drug-sensitive viral population to the level of appearance of resistant variants. In vivo, viral resistance is influenced by three major factors including the genetic barrier to resistance, in vivo fitness of the viral variant population and drug exposure. Different studies have indicated that the variants show resistance to NS3/4A protease inhibitors, nucleoside/nucleotide analogues, non-nucleoside RNA-dependent RNA polymerase inhibitors, NS5A as well as cyclophilin inhibitors[130]. In view of these alterations, the drug resistant variants may cause a serious challenge to infection and therefore, this problem needs a solution by more extensive investigations.

    Conclusion

    This study concludes that the use of PegIFN-α and ribavirin is still a major part of standard of care (SOC) and the control of HCV infection. The addition of new drugs including DAAs, cyclophilins and miravirsen, etc. has made a significant improvement in SVR even in those patients where HCV genotypes remain resistant to PegIFN-α plus ribavirin drug regimen. These drugs target and inhibit viral proteases and cell receptor proteins as well as enzymes facilitating viral entry into the cell and viral replication and assembly inside the cell. A check on viral entry as well as their cell to cell transmission or further replication by the use of these drugs achieves the aim of treatment. In spite of an increase in SVR, the effect of DAAs is altered by the viral and cellular factors. Basic viral load and viral genotypes were found to show a significant effect on therapeutic outcome. Similarly, some disease conditions or cellular genomic polymorphism like IL28B polymorphism also have an impact on drug therapy. The development of drug resistant HCV variants during viral propagation still remains a serious challenge and needs to be resolved by different combination or development of new drugs. Studies are in progress looking towards new aspects of drug therapy against HCV infection.

    Declarations

    Acknowledgments

    We appreciate the infrastructure provided by All India Institute of Medical Sciences, New Delhi, India, for the conduct of this study.

    Authors’ contributions

    All authors have made equal contributions in the performance of study, compilation of data and preparation of the manuscript.

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    None.

    Conflicts of interest

    The authors declare that there are no conflicts of interest related to this study.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.

    Copyright

    © The Author(s) 2018.

    References

    • 1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013;57:1333-42.

      DOIPubMed
    • 2. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007;13:2436-41.

      DOIPubMedPMC
    • 3. Lavanchy D. The global burden of hepatitis C. Liver Int 2009;29 Suppl1:74-81.

      DOIPubMed
    • 4. McHutchison JG, Bacon BR. Chronic hepatitis C: an age wave of disease burden. Am J Manag Care 2005;11:S286-95; quiz S307-11.

    • 5. Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 2017;9:1305-14.

      DOIPubMedPMC
    • 6. Chevaliez S, Pawlotsky JM. HCV Genome and Life Cycle. In: Tan SL, editor. Hepatitis C Viruses: Genomes and Molecular Biology. UK: Norfolk; 2006 .

      PMC
    • 7. Khaliq S, Jahan S, Pervaiz A. Sequence variability of HCV core region: important predictors of HCV induced pathogenesis and viral production. Infect Genet Evol 2011;11:543-56.

      DOIPubMed
    • 8. Drummer HE, Maerz A, Poumbourios P. Cell surface expression of functional hepatitis C virus E1 and E2 glycoproteins. FEBS Lett 2003;546:385-90.

      DOI
    • 9. Steinmann E, Penin F, Kallis S, Patel AH, Bartenschlager R, Pietschmann T. Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. PLoS Pathog 2007;3:e103.

      DOIPubMedPMC
    • 10. Steinmann E, Pietschmann T. Hepatitis C virus p7-a viroporin crucial for virus assembly and an emerging target for antiviral therapy. Viruses 2010;2:2078-95.

      DOIPubMedPMC
    • 11. Gallinari P, Brennan D, Nardi C, Brunetti M, Tomei L, Steinkühler C, De Francesco R. Multiple enzymatic activities associated with recombinant NS3 protein of hepatitis C virus. J Virol 1998;72:6758-69.

      PubMedPMC
    • 12. Stapleford KA, Lindenbach BD. Hepatitis C virus NS2 coordinates virus particle assembly through physical interactions with the E1-E2 glycoprotein and NS3- NS4A enzyme complexes. J Virol 2011;85:1706-17.

      DOIPubMedPMC
    • 13. Morikawa K, Lange CM, Gouttenoire J, Meylan E, Brass V, Penin F, Moradpour A. Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepat 2011;18:305-15.

      DOIPubMed
    • 14. Gouttenoire J, Penin F, Moradpour D. Hepatitis C virus nonstructural protein 4B:a journey into unexplored territory. Rev Med Virol 2010;20:117-29.

      DOIPubMed
    • 15. Macdonald A, Crowder K, Street A, McCormick C, Harris M. The hepatitis C virus NS5A protein binds to members of the Src family of tyrosine kinases and regulates kinase activity. J Gen Virol 2004;85:721-9.

      DOIPubMed
    • 16. Reed KE, Xu J, Rice CM. Phosphorylation of the hepatitis C virus NS5A protein in vitro and in vivo: properties of the NS5A-associated kinase. J Virol 1997;71:7187-97.

      PubMedPMC
    • 17. Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol 2007;5:453-63.

      DOIPubMed
    • 18. Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Disease. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-74.

      DOIPubMed
    • 19. Chhatwal J, He T, Hur C, Lopez-Olivo MA. Direct-acting antiviral agents for patients with hepatitis C virus genotype 1 infection are cost-saving. Clin Gastroenterol Hepatol 2017;15:827-37.e8.

      DOIPubMed
    • 20. Buhler S, Bartenschlager R. New targets for antiviral therapy of chronic hepatitis C. Liver Int 2012;32:9-16.

      DOIPubMed
    • 21. Aghemo A, De Francesco R. New horizons in hepatitis C antiviral therapy with direct acting antivirals. Hepatology 2013;58:428-38.

      DOIPubMed
    • 22. Temesgen Z, Rizza SA. Daclatasvir for the treatment of chronic hepatitis C virus infection. Drugs Today (Barc) 2015;51:277-88.

      DOIPubMed
    • 23. Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, Afdhal N, Vierling JM, Gordon SC, Anderson JK, Hyland RH, Dvory-Sobol H, An D, Hindes RG, Albanis E, Symonds WT, Berrey MM, Nelson DR, Jacobson IM. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment- naïve patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013;381:2100-7.

      DOI
    • 24. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, Nelson DR, Dieterich DT, Jacobson IM, Jensen D, Abrams GA, Darling JM, Rodriguez-Torres M, Reddy KR, Sulkowski MS, Bzowej NH, Hyland RH, Mo H, Lin M, Mader M, Hindes R, Albanis E, Symonds WT, Berrey MM, Muir A. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013;13:401-8.

      DOI
    • 25. Issur M, Gotte M. Resistance patterns associated with HCV NS5A inhibitors provide limited insight into drug binding. Viruses 2014;6:4227-41.

      DOIPubMedPMC
    • 26. Nelson DR, Benhamou Y, Chuang WL, Lawitz EJ, Rodriguez- Torres M, Flisiak R, Rasenack JW, Kryczka W, Lee CM, Bain VG, Pianko S, Patel K, Cronin PW, Pulkstenis E, Subramanian GM, McHutchison JG. Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3. Gastroenterology 2010;139:1267-76.

      DOIPubMedPMC
    • 27. Zeuzem S, Sulkowski MS, Lawitz EJ, Rustgi VK, Rodriguez- Torres M, Bacon BR, Grigorescu M, Tice AD, Lurie Y, Cianciara J, Muir AJ, Cronin PW, Pulkstenis E, Subramanian GM, McHutchison JG. Albinterferon alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1. Gastroenterology 2010;139:1257-66.

      DOIPubMed
    • 28. Muir AJ, Shiffman ML, Zaman A, Yoffe B, de la Torre A, Flamm S, Gordon SC, Marotta P, Vierling JM, Lopez- Talavera JC, Byrnes-Blake K, Fontana D, Freeman J, Gray T, Hausman D, Hunder NN, Lawitz E. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology 2010;52:822-32.

      DOIPubMed
    • 29. Zhu Y, Chen S. Antiviral treatment of hepatitis C virus infection and factors affecting efficacy. World J Gastroenterol 2013;19:8963-73.

      DOIPubMedPMC
    • 30. Cummings MD, Lindberg J, Lin TI, de Kock H, Lenz O, Lilja E, Felländer S, Baraznenok V, Nyström S, Nilsson M, Vrang L, Edlund M, Rosenquist A, Samuelsson B, Raboisson P, Simmen K. Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3/NS4A protease target. Angew Chem Int Ed Engl 2010;49:1652-5.

      DOIPubMed
    • 31. Sato K, Kobayashi T, Yamazaki Y, Takakusagi S, Horiguchi N, Kakizaki S, Kusano M, Yamada M. Spontaneous remission of hepatitis B virus reactivation during direct-acting antiviral agent-based therapy for chronic hepatitis C. Hepatol Res 2017;47:1346-53.

      DOIPubMed
    • 32. Guidelines for the Screening Care and Treatment of Persons with Chronic Hepatitis Infection: Updated Version C. Geneva: World Health Organization; 2016.

    • 33. Hopkins S, Gallay P. Cyclophilin inhibitors: an emerging class of therapeutics for the treatment of chronic hepatitis C infection. Viruses 2012;4:2558-77.

      DOIPubMedPMC
    • 34. Hopkins S, Bobardt M, Chatterji U, Garcia-Rivera JA, Lim P, Gallay PA. The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes. Antimicrob Agents Chemother 2012;56:3888-97.

      DOIPubMedPMC
    • 35. Rocco A, Compare D, Coccoli P, Esposito C, Di Spirito A, Barbato A, Strazzullo P, Nardone G. Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus. Gut 2013;62:766-73.

      DOIPubMed
    • 36. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol 2011;17:5184-90.

      DOIPubMedPMC
    • 37. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol 2012;18:800-5.

      DOIPubMedPMC
    • 38. Malaguarnera M, Vacante M, Giordano M, Motta M, Bertino G, Pennisi M, Neri S, Malaguarnera M, Li Volti G, Galvano F. L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-α 2b plus ribavirin. World J Gastroenterol 2011;17:4414-20.

      DOIPubMedPMC
    • 39. Qian XJ, Zhu YZ, Zhao P, Qi ZT. Entry inhibitors: new advances in HCV treatment. Emerg Microbes Infect 2016;5:e3.

      DOIPubMedPMC
    • 40. Jiang J, Cun W, Wu X, Shi Q, Tang H, Luo G. Hepatitis C virus attachment mediated by apolipoprotein E binding to cell surface heparan sulfate. J Virol 2012;86:7256-67.

      DOIPubMedPMC
    • 41. Helle F, Wychowski C, Vu-Dac N, Gustafson KR, Voisset C, Dubuisson J. Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem 2006;281:25177-83.

      DOIPubMed
    • 42. Holmskov U, Thiel S, Jensenius JC. Collections and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol 2003;21:547-78.

      DOIPubMed
    • 43. Ciesek S, von Hahn T, Colpitts CC, Schang LM, Friesland M, Steinmann J, Manns MP, Ott M, Wedemeyer H, Meuleman P, Pietschmann T, Steinmann E. The green tea polyphenol, epigallocatechin-3- gallate, inhibits hepatitis C virus entry. Hepatology 2011;54:1947-55.

      DOIPubMed
    • 44. Calland N, Albecka A, Belouzard S, Wychowski C, Duverlie G, Descamps V, Hober D, Dubuisson J, Rouillé Y, Séron K. (-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. Hepatology 2012;55:720-9.

      DOIPubMed
    • 45. Calland N, Sahuc ME, Belouzard S, Pène V, Bonnafous P, Mesalam AA, Deloison G, Descamps V, Sahpaz S, Wychowski C, Lambert O, Brodin P, Duverlie G, Meuleman P, Rosenberg AR, Dubuisson J, Rouillé Y, Séron K. Polyphenols inhibit hepatitis C virus entry by a new mechanism of action. J Virol 2015;89:10053-63.

      DOIPubMedPMC
    • 46. Redwan EM, Uversky VN, El-Fakharany EM, Al-Mehdar H. Potential lactoferrin activity against pathogenic viruses. C R Biol 2014;337:581-95.

      DOIPubMed
    • 47. Hong W, Lang Y, Li T, Zeng Z, Song Y, Wu Y, Li W, Cao Z. A p7 ion channel- derived peptide inhibits hepatitis C virus infection in vitro. J Biol Chem 2015;290:23254-63.

      DOIPubMedPMC
    • 48. Brimacombe CL, Grove J, Meredith LW, Hu K, Syder AJ, Flores MV, Timpe JM, Krieger SE, Baumert TF, Tellinghuisen TL, Wong-Staal F, Balfe P, McKeating JA. Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission. J Virol 2011;85:596-605.

      DOIPubMedPMC
    • 49. Lavillette D, Tarr AW, Voisset C, Donot P, Bartosch B, Bain C, Patel AH, Dubuisson J, Ball JK, Cosset F. Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus. Hepatology 2005;41:265-74.

      DOIPubMed
    • 50. Gottwein JM, Scheel TK, Jensen TB, Lademann JB, Prentoe JC, Knudsen ML, Hoegh AM, Bukh J. Development and characterization of hepatitis C virus genotype 1-7 cell culture systems: role of CD81 and scavenger receptor class B type I and effect of antiviral drugs. Hepatology 2009;49:364-77.

      DOIPubMed
    • 51. Vanwolleghem T, Bukh J, Meuleman Vanwolleghem T P, Bukh J, Meuleman P, Desombere I, Meunier JC, Alter H, Purcell RH, Leroux-Roels G. Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver- chimeric mice from infection with a homologous hepatitis C virus strain. Hepatology 2008;47:1846-55.

      DOIPubMed
    • 52. Meuleman P, Hesselgesser J, Paulson M, Vanwolleghem T, Desombere I, Reiser H, Leroux-Roels G. Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo. Hepatology 2008;48:1761-8.

      DOIPubMed
    • 53. Ji C, Liu Y, Pamulapati C, Bohini S, Fertig G, Schraeml M, Rubas W, Brandt M, Ries S, Ma H, Klumpp K. Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody. Hepatology 2015;61:1136-44.

      DOIPubMed
    • 54. Zeisel MB, Koutsoudakis G, Schnober EK, Haberstroh A, Blum HE, Cosset FL, Wakita T, Jaeck D, Doffoel M, Royer C, Soulier E, Schvoerer E, Schuster C, Stoll- Keller F, Bartenschlager R, Pietschmann T, Barth H, Baumert TF. Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81. Hepatology 2007;46:1722-31.

      DOIPubMed
    • 55. Lavie M, Voisset C, Vu-Dac N, Zurawski V, Duverlie G, Wychowski C, Dubuisson J. Serum amyloid A has antiviral activity against hepatitis C virus by inhibiting virus entry in a cell culture system. Hepatology 2006;44:1626-34.

      DOIPubMed
    • 56. Masson D, Koseki M, Ishibashi M, Larson CJ, Miller SG, King BD, Tall AR. Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor. Arterioscler Thromb Vasc Biol 2009;29:2054-60.

      DOIPubMedPMC
    • 57. Syder AJ, Lee H, Zeisel MB, Grove J, Soulier E, Macdonald J, Chow S, Chang J, Baumert TF, McKeating JA, McKelvy J, Wong-Staal F. Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. J Hepatol 2011;54:48-55.

      DOIPubMed
    • 58. Krieger SE, Zeisel MB, Davis C, Thumann C, Harris HJ, Schnober EK, Mee C, Soulier E, Royer C, Lambotin M, Grunert F, Dao Thi VL, Dreux M, Cosset FL, McKeating JA, Schuster C, Baumert TF. Inhibition of hepatitis C virus infection by anticlaudin- 1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations. Hepatology 2010;51:1144-57.

      DOIPubMed
    • 59. Fofana I, Krieger SE, Grunert F, Glauben S, Xiao F, Fafi-Kremer S, Soulier E, Royer C, Thumann C, Mee CJ, McKeating JA, Dragic T, Pessaux P, Stoll-Keller F, Schuster C, Thompson J, Baumert TF. Monoclonal anti-claudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes. Gastroenterology 2010;139:953-64.

      DOIPubMed
    • 60. Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FHT, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF. Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol 2015;5:549-54.

      DOIPubMedPMC
    • 61. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, Davis C, Mee CJ, Turek M, Gorke S, Royer C, Fischer B, Zahid MN, Lavillette D, Fresquet J, Cosset FL, Rothenberg SM, Pietschmann T, Patel AH, Pessaux P, Doffoël M, Raffelsberger W, Poch O, McKeating JA, Brino L, Baumert TF. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 2011;17:589-95.

      DOIPubMedPMC
    • 62. Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouillé Y. Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol 2006;80:6964-72.

      DOIPubMedPMC
    • 63. Blanchard AA, Watson PH, Shiu RP, Leygue E, Nistor A, Wong P, Myal Y. Differential expression of claudin 1, 3, and 4 during normal mammary gland development in the mouse. DNA Cell Biol 2006;25:79-86.

      DOIPubMed
    • 64. Blaising J, Levy PL, Polyak SJ, Stanifer M, Boulant S, Pecheur EI. Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking. Antiviral Res 2013;100:215-9.

      DOIPubMed
    • 65. Meertens L, Bertaux C, Dragic T. Hepatitis C virus entry requires a critical postinternalization step and delivery to early endosomes via clathrin-coated vesicles. J Virol 2006;80:11571-8.

      DOIPubMedPMC
    • 66. Polyak SJ, Morishima C, Shuhart MC, Wang CC, Liu Y, Lee DY. Inhibition of T- cell inflammatory cytokines, hepatocyte NF-kB signaling, and HCV infection by standardized Silymarin. Gastroenterology 2007;132:1925-36.

      DOIPubMed
    • 67. Behrens SE, Tomei L, De Francesco R. Identification and properties of the RNA- dependent RNA polymerase of hepatitis C virus. EMBO J 1996;15:12-22.

      PubMedPMC
    • 68. Lohmann V, Körner F, Herian U, Bartenschlager R. Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. J Virol 1997;71:8416-28.

      PubMedPMC
    • 69. Morikawa K, Lange CM, Gouttenoire J, Meylan E, Brass V, Penin F, Moradpour A. Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepat 2011;18:305-15.

      DOIPubMed
    • 70. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bös M, Cameron DR, Cartier M, Cordingley MG, Faucher AM, Goudreau N, Kawai SH, Kukolj G, Lagacé L, LaPlante SR, Narjes H, Poupart MA, Rancourt J, Sentjens RE, St George R, Simoneau B, Steinmann G, Thibeault D, Tsantrizos YS, Weldon SM, Yong CL, Llinàs-Brunet M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003;426:186-9.

      DOIPubMed
    • 71. Delang L, Neyts J, Vliegen I, Abrignani S, Neddermann P, De Francesco R. Hepatitis C virus-specific directly acting antiviral drugs. Curr Top Microbiol Immunol 2013;369:289-320.

      DOI
    • 72. Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, Coleman PJ, Dimuzio JM, Ferrara M, Di Filippo M, Gates AT, Graham DJ, Harper S, Hazuda DJ, Huang Q, McHale C, Monteagudo E, Pucci V, Rowley M, Rudd MT, Soriano A, Stahlhut MW, Vacca JP, Olsen DB, Liverton NJ, Carroll SS. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012;56:4161-7.

      DOIPubMedPMC
    • 73. Pawlotsky JM. NS5A inhibitors in the treatment of hepatitis C. J Hepatol 2013;59:375-82.

      DOIPubMed
    • 74. Kaneko T, Tanji Y, Satoh S, Hijikata M, Asabe S, Kimura K, Shimotohno K. Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome. Biochem Biophys Res Commun 1994;205:320-6.

      DOIPubMed
    • 75. Quintavalle M, Sambucini S, Summa V, Orsatti L, Talamo F, De Francesco R, Neddermann P. Hepatitis C virus NS5A is a direct substrate of casein kinase I- alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitors. J Biol Chem 2007;282:5536-44.

      DOIPubMed
    • 76. Chen YC, Su WC, Huang JY, Chao TC, Jeng KS, Machida K, Lai MM. Polo-like kinase 1 is involved in hepatitis C virus replication by hyperphosphorylating NS5A. J Virol 2010;84:7983-93.

      DOIPubMedPMC
    • 77. Bartenschlager R, Lohmann V, Penin F. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol 2013;11:482-96.

      DOIPubMed
    • 78. Paul D, Romero-Brey I, Gouttenoire J, Stoitsova S, Krijnse-Locker J, Moradpour D, Bartenschlager R. NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes. J Virol 2011;85:6963-76.

      DOIPubMedPMC
    • 79. Rehman S, Ashfaq UA, Javed T. Antiviral drugs against hepatitis C virus. Genet Vaccines Ther 2011;9:11.

      DOIPubMedPMC
    • 80. Yang F, Robotham JM, Nelson HB, Irsigler A, Kenworthy R, Tang H. Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 2008;82:5269-78.

      DOIPubMedPMC
    • 81. Kaul A, Stauffer S, Berger C, Pertel T, Schmitt J, Kallis S, Zayas M, Lohmann V, Luban J, Bartenschlager R. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog 2009;5:e1000546.

      DOIPubMedPMC
    • 82. Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003;38:1282-8.

      DOIPubMed
    • 83. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 2005;309:1577-81.

      DOIPubMed
    • 84. Shimakami T, Yamane D, Jangra RK, Kempf BJ, Spaniel C, Barton DJ, Lemon SM. Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proc Natl Acad Sci U S A 2012;109:941-6.

      DOIPubMedPMC
    • 85. Henke JI, Goergen D, Zheng J, Song Y, Schüttler CG, Fehr C, Jünemann C, Niepmann M. microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J 2008;27:3300-10.

      DOIPubMedPMC
    • 86. Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Ørum H. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010;327:198-201.

      DOIPubMedPMC
    • 87. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013;368:1685-94.

      DOIPubMed
    • 88. Qu X, Pan X, Weidner J, Yu W, Alonzi D, Xu X, Butters T, Block T, Guo JT, Chang J. Inhibitors of endoplasmic reticulum alpha-glucosidases potently suppress hepatitis C virus virion assembly and release. Antimicrob Agents Chemother 2011;55:1036-44.

      DOIPubMedPMC
    • 89. Ouzounov S, Mehta A, Dwek RA, Block TM, Jordan R. The combination of interferon alpha-2b and n-butyl deoxynojirimycin has a greater than additive antiviral effect upon production of infectious bovine viral diarrhea virus (BVDV) in vitro: implications for hepatitis C virus (HCV) therapy. Antiviral Res 2002;55:425-35.

      DOI
    • 90. Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 2007;132:1979-98.

      DOIPubMed
    • 91. Takkenberg B, de Bruijne J, Weegink C, Jansen P, Reesink H. Novel therapies in hepatitis B and C. Curr Gastroenterol Rep 2008;10:81-90.

      DOIPubMed
    • 92. Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg AR, Farese RV Jr, Ott M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 2010;16:1295-8.

      DOIPubMedPMC
    • 93. Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV Jr. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 2008;49:2283-301.

      DOIPubMedPMC
    • 94. Jacobson IM, Brown RS, Freilich B, Afdhal N, Kwo PY, Santoro J, Becker S, Wakil AE, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Pauly MP, Mukhopadhyay P, Griffel LH, Brass CA. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients:a randomized trial. Hepatology 2007;46:971-81.

      DOIPubMed
    • 95. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97-103.

      DOIPubMed
    • 96. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Solá R, Shafran SD, Barange K, Lin A, Soman A, Zeuzem S. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124-34.

      DOIPubMed
    • 97. Buskila D. Hepatitis C-associated rheumatic disorders. Rheum Dis Clin North Am 2009;35:111-23.

      DOIPubMed
    • 98. Kamal SM, Ahmed A, Mahmoud S, Nabegh L, El Gohary I, Obadan I, Hafez T, Ghoraba D, Aziz AA, Metaoei M. Enhanced efficacy of pegylated interferon alpha-2a over pegylated interferon and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of life analysis. Liver Int 2011;31:401-11.

      DOIPubMed
    • 99. Stetson DB, Medzhitov R. Type I interferons in host defense. Immunity 2006;25:373-81.

      DOIPubMed
    • 100. Gale M Jr. Effector genes of interferon action against hepatitis C virus. Hepatology 2003;37:975-8.

      DOIPubMed
    • 101. Gilmour KC, Reich NC. Signal transduction and activation of gene transcription by interferons. Gene Expr 1995;5:1-18.

      PubMed
    • 102. Taylor DR, Shi ST, Lai MM. Hepatitis C virus and interferon resistance. Microbes Infect 2000;2:1743-56.

      DOI
    • 103. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y, Jones EA. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 1986;315:1575-8.

      DOIPubMed
    • 104. Cavalcante LN, Lyra AC. Predictive factors associated with hepatitis C antiviral therapy response. World J Hepatol 2015;7:1617-31.

      DOIPubMedPMC
    • 105. Gale M Jr, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature 2005;436:939-45.

      DOIPubMed
    • 106. Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 2013;19:7896-909.

      DOIPubMedPMC
    • 107. Shao RX, Zhang L, Peng LF, Sun E, Chung WJ, Jang JY, Tsai WL, Hyppolite G, Chung RT. Suppressor of cytokine signaling 3 suppresses hepatitis C virus replication in an mTORdependent manner. J Virol 2010;84:6060-9.

      DOIPubMedPMC
    • 108. Lin W, Choe WH, Hiasa Y, Kamegaya Y, Blackard JT, Schmidt EV, Chung RT. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology 2005;128:1034-41.

      DOIPubMed
    • 109. Lin W, Kim SS, Yeung E, Kamegaya Y, Blackard JT, Kim KA, Holtzman MJ, Chung RT. Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol 2006;80:9226-35.

      DOIPubMedPMC
    • 110. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon- inducible protein kinase PKR by HCV E2 protein. Science 1999;285:107-10.

      DOIPubMed
    • 111. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A 2005;102:17717-22.

      DOIPubMedPMC
    • 112. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005;437:1167-72.

      DOIPubMed
    • 113. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, Ikeda M, Ray SC, Gale M Jr, Lemon SM. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A 2005;102:2992-7.

      DOIPubMedPMC
    • 114. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid inducible gene-I signaling. Proc Natl Acad Sci U S A 2005;102:2986-91.

      DOIPubMedPMC
    • 115. Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003;300:1145-8.

      DOIPubMed
    • 116. Xu J, Liu S, Xu Y, Tien P, Gao G. Identification of the nonstructural protein 4B of hepatitis C virus as a factor that inhibits the antiviral activity of interferon-alpha. Virus Res 2009;141:55-62.

      DOIPubMed
    • 117. Gale MJ Jr, Korth MJ, Katze MG. Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance. Clin Diagn Virol 1998;10:157-62.

      DOI
    • 118. Gale MJ Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997;230:217-27.

      DOIPubMed
    • 119. Gong GZ, Cao J, Jiang YF, Zhou Y, Liu B. 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 2007;13:4080-4.

      DOIPubMedPMC
    • 120. Lan KH, Lan KL, Lee WP, Sheu ML, Chen MY, Lee YL, Yen SH, Chang FY, Lee SD. HCV NS5A inhibits interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines. J Hepatol 2007;46:759-67.

      DOIPubMed
    • 121. Kumthip K, Maneekarn N. The role of HCV proteins on treatment outcomes. Virol J 2015;12:217.

      DOIPubMedPMC
    • 122. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399-401.

      DOIPubMed
    • 123. Guss D, Sherigar J, Rosen P, Mohanty SR. Diagnosis and management of hepatitis C infection in primary care settings. J Gen Intern Med 2018;33:551-7.

      DOIPubMed
    • 124. Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147:677-84.

      DOIPubMed
    • 125. Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL, Lee WM, Di Bisceglie AM, Bonkovsky HL, Dienstag JL, Morishima C, Lindsay KL, Lok AS, HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 2010;52:833-44.

      DOIPubMedPMC
    • 126. Chen Yi Mei SLG, Thompson AJ, Christensen B, Cunningham G, McDonald L, Bell S, Iser D, Nguyen T, Desmond PV. Sustained virological response halts fibrosis progression: a long-term follow-up study of people with chronic hepatitis C infection. PLoS One 2017;12:e0185609.

      DOIPubMedPMC
    • 127. Terrault NA, Hassanein TI. Management of the patient with SVR. J Hepatol 2016;65 Suppl 1:S120-9.

      DOIPubMed
    • 128. Ahmed A, Felmlee DJ. Mechanisms of hepatitis C viral resistance to direct acting antivirals. Viruses 2015;7:6716-29.

      DOIPubMedPMC
    • 129. Sesmero E, Thorpe IF. Using the hepatitis C virus RNA-dependent RNA polymerase as a model to understand viral polymerase structure, function and dynamics. Viruses 2015;7:3974-94.

      DOIPubMedPMC
    • 130. Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology 2011;53:1742-51.

      DOIPubMed

    Article Access Statistics

    • Viewed: 528
    • Downloaded: 53
    • Cited: Crossref1

    See Updates

    Recommended Articles

    Table of Contents