HCV Genotype 4; A Brief Review

Muhammad Sohail Afzal, Amany Abd Elreheem, Ahmed Ragaa, Ahmed Wahid

Muhammad Sohail Afzal, Atta ur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan
Amany Abd Elreheem, Ahmed Ragaa, Ahmed Wahid, Department of Biochemistry, Faculty of Pharmacy, Minia University, Egypt

Correspondence to: Ahmed Wahid, Department of Biochemistry, Faculty of Pharmacy, Minia University, Egypt.
Emial: ahmed_wahid@mu.edu.eg
Received: September 30, 2013
Revised: November 25, 2013
Accepted: November 30, 2013
Published online: Febuary 21, 2014


Hepatitis C virus (HCV) is a known leading cause of chronic liver diseases and hepatocellular carcinoma (HCC). The current available treatment depends on the co-administration of peginterferon and ribavirin. Current treatment drugs are extremely expensive, not effective in all patients with different genotypes and are associated with serious side effects that may lead even to death in some cases. Phylogenetic analysis has led to the classification of hepatitis C virus (HCV) into more than 7 genotypes depending on several criteria, amongst them is their worldwide distribution, transmission and disease progression. The lack of availability of an effective vaccine allowed education programs to be the most suitable interventions in the control of HCV spread. Here in this review we will discuss the advanced tools to study HCV genotype 4, and current treatments and vaccination trials of HCV and finally the progress of HCV into hepatocellular carcinoma.

Key words: HCV; Genotype 4; Treatment; Vaccine trials

© 2014 The Authors. Published by ACT Publishing Group Ltd.

Afzal MS, Elreheem AA, Ragaa A, Wahid A. HCV Genotype 4; A Brief Review. Journal of Gastroenterology and Hepatology Research 2014; 3(2): 968-976 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/606


Hepatitis C virus (HCV) is a complex liver disease. Its medical importance and the need to rapidly identify new therapeutic approaches has resulted in intensive study of its causative agent. HCV infection is a major public health problem with more than 160 million people infected worldwide, this figure represents nearly 3% of the world’s total population according to the estimates of the World Health Organization (WHO), and 2-3 million new cases per year[1,2].

HCV is one of the main health problems particularly in Egypt, where HCV genotype 4 predominates, as it infects more than 20% of its general population according to WHO estimates. The highest prevalence of antibodies to hepatitis C virus (HCV) in the world was reported in Egypt, where HCV genotype 4 predominates[3].

There are many possible reasons that lie behind the wide transmission of HCV in Egypt. Amongst these is dental treatment as a possible source for transmission of HCV infection[4]. Patients undergoing hemodialysis were also found to be at great risk of HCV transmission[5]. Moreover, the use of glass syringes was reported before in south Italy to be one of the old modes of transmission of infection[6]. And finally, major risk factors for HCV infection in Korea were mostly related to inapropriate healthcare procedures such as blood transfusion, needle stick injury, surgery, dental procedure, and tattooing[7].


HCV is a small enveloped virus, classified in the Hepacivirus genus within the Flaviviridae family. The 5′-UTR of the HCV genome contains a large structured domain that serves as an internal ribosomal entry site (IRES)[1,8,9]. Upon HCV infection, the normal cap-dependent translation process is strongly inhibited, and infected cells instead shift most of their protein synthesis capacity to viral polyprotein production. The HCV IRES element recruits the 40S ribosomal subunit directly to initiate viral RNA translation bypassing the requirement for several translation initiation factors[10,11]. HCV positive-strand RNA genome then encodes a single polyprotein which is processed by cellular and viral proteases into 10 mature proteins (4 structural and 6 non-structural proteins)[12].

Our understanding of the HCV morphogenesis process is still in its infancy. Different viral components were identified as players in the morphogenesis process. As expected, the structural proteins are essential in the virus makeup. Among these components, HCV envelope glycoproteins, E1 and E2, are of particular interest since in addition to their role in assembly, they are also the major players during the entry process. HCV envelope glycoproteins E1 and E2 are type-I transmembrane proteins that consist of a C-terminal transmembrane domain and a large N-terminal ectodomain, which is heavily modified by N-linked glycans[13]. Importantly, entry and assembly functions need to be tightly controlled in order to occur at the appropriate location and time[14]. These two proteins assemble as a non-covalent heterodimer within the endoplasmic reticulum (ER) of infected cells, whereas they form large disulfide-linked complexes on the virion surface[15]. They are indeed involved in receptor binding, and mediate the fusion process between the viral envelope and an endosomal host cell membrane. E1 and E2 glycoproteins are deeply involved in the vaccination trials against HCV.


HCV is further classified into at least seven major genotypes that differ by about 30 percent in their nucleotide sequence. These genotypes (1, 2, 3, 4, 5, 6 & 7) show differences based on their worldwide distribution, transmission and disease progression (as mentioned above). There are a lot of differences amongst these genotypes in their nucleotide substitutions in the viral genome (31-33% nucleotide sequence difference between different genotypes) and more than 100 subtypes (20-25% difference between different subtypes of the same genotype) present in different regions of the world[16].

There exist a big debate on the classification of different genotypes of HCV. Some investigators proposed up to 11 different HCV genotypes, and according to others HCV is only divided into 6 major genotypes, genotypes 6-11 being variants of genotype 6. According to this theory, genotypes 6-11 should be classified as a single genotype i.e. type 6[17]. As shown in recently, genotypes 1-3 are distributed worldwide, and types 1a and 1b are the most prevalent globally. Genotype 1b is most prevalent in Japan (70%)[18-20]. Genotype 1 is more prevalent in Europe[21,22]. In South-East Asia genotype 3 is most common up to 90 % patients[23-25]. Whereas genotype 4 is most common in central Africa, Egypt and Middle East[26]. It is noteworthy that genotype 4 is quasi-exclusive (91%) in Egypt[27]. Vietnamese population harbors geographically isolated genotypes 7, 8 and 9 and these genotypes so far identified from this region only[28]. Genotypes 10 and 11 are only identified in Indonesian HCV infected patients[29].


HCV circulates in infected patients at relatively low titers and forms complexes with serum components such as lipoproteins[30,31]. For reasons that remain partly unknown, serum-derived HCV cannot be propagated in cell culture. HCV research has been hindered by these restrictions and has largely depended on surrogate systems. For instance, replication-deficient retroviruses pseudotyped with HCV envelope glycoproteins (HCVpp)[32] were used to study HCV entry[33]. Similarly, replicon systems allowed investigation of HCV replication (for a review, see[34]). However, until 2005, there was no system available to reproduce HCV assembly and secretion, which remained mostly elusive. Likewise, 21 years after HCV discovery, its structure remains unknown. Nevertheless, in 2005, several teams finally succeeded in propagating HCV in cell culture (cell-cultured HCV, HCVcc)[35-37], which allowed to confirm most of the previous data on viral entry and which facilitated antiviral testing. Moreover, this system allowed for the first time the investigation of virus assembly.

After its identification, there were many attempts to define HCV genotype 4 by analyzing the partial sequences of variants. HCV genotype 4 variants were amplified from patients’ sera. 5’ UTR, core, E1, E2, NS3, NS4, NS5 and 3’UTR regions were sequenced and analyzed[38-41]. In 1997 Chamberlain et al reported the complete nucleotide sequence of the HCV genotype 4a Egyptian variant, ED43 (GenBank accession no. Y11604)[42]. Furthermore, in 2007 Timm et al described the full-length sequence of HCV genotype 4d, the most prevalent subtype in sub-Saharan African infections[43]. HCV genotype 4 and its subtypes reference sequences can be found in the (LosAlamos HCV database) (http://hcv.lanl.gov/content/hcv-db/classification/genotable.html).


In 1999, HCV replicon system was developed for genotype 1b. This system was developed by trimming the viral genome necessary for viral replication i.e. NS3-NS5B along with 3’, 5’ UTR regions[44]. Due to smaller size than authentic viral genome it was possible to insert a heterologous dominant selectable marker (e.g., Neomycin Phosphotransferase, neo) without exceeding the natural length of the HCV genome. Replicons were often bicistronic constructs, with Neomycin Phosphotransferase translation driven by the HCV IRES, followed by the HCV NS3-3' UTR under the control of a second IRES derived from encephalomyocarditis virus (EMCV).

Previously HCV replicon systems have been successfully established for only wild type or adapted genotypes 1a[44-56]. Very recently, Charles Rice lab developed repilicon systems for 3a and 4a genotypes[57]. The prototype strain ED43 (4a) was used to generate G418-selectable subgenomic replicons. To make these replicons more useful for high-throughput screening and evaluation of antiviral compounds, they were modified to express a chimeric fusion protein of firefly luciferase and neomycin phosphotransferase to yield stable replicon-expressing cells.


In the absence of HCV cell culture system for studying entire viral life cycle, surrogate models to study the role of HCV glycoproteins in virus entry were developed. The most successful model to investigate early steps of HCV infection was the establishment of retroviral pseudotypes bearing unmodified HCV glycoproteins (HCVpp)[58,59]. HCVpp is based on the co-transfection of 293T kidney cells with expression vectors encoding HCV E1 and E2, gag-pol proteins of either murine leukemia virus (MLV) or human immunodeficiency virus (HIV) and finally a retroviral genome encoding a reporter gene (luciferase). The HCVpp can be used for antibody neutralization studies as the attachment and receptor interaction of these retroviral pseudotypes is governed by the functional HCV E1-E2 protein complex incorporated into the envelope of these particles. It is worth noting that the HCVpp system for HCV genotype 4 were developed by three independent groups[60-62] which were widely used for viral entry and receptor binding investigation studies.


The development of efficient culture systems for studying the important genotype specific antiviral targets NS3, NS5A, in the context of complete virus, allowed the investigation of small direct acting antiviral compounds. Indeed, NS5A is considered one of the promising targets for small anti HCV compounds which are already in clinical trials[63]. Much is still to be learned about the role of the highly diverse NS5A functions in genotype 2a; and; furthermore for most other genotypes, NS5A has not been studied at all. Recently, infectious genotype-specific HCV NS5A cell culture systems for HCV genotype 4 along with other HCV genotypes was developed by replacing the complete NS5A of the J6/JFH1 recombinant[64] with NS5A from ED43 (4a)[65]. Another very important target is the HCV non-structural protein NS3. The recently developed full-length replication-competent clone Jc1 (pFK JFH1/J6/C-846), which showed very high replication efficiency in Huh7.5 cells, was used to develop recombinant virus expressing the NS3 protease of HCV genotype 4 and all other genotypes[66]. This recombinant virus allowed the direct monitoring of antiviral drug inhibition for specific proteases through assessment of reduction in both supernatant infectivity and replication kinetics. This genotype specific protease system also provided a phenotypic assay for rapid assessment of emerging resistance during therapy and the influence of specific mutations on treatment outcome.


The year 2005 was a mile stone in HCV research when Wakita et al[67] developed the genotype 2a JFH1 cell culture system from a Japanese Fuliminant Hepatitis patient. JFH1 is an efficient in vitro system and allows the investigation of the complete infectious virus life cycle. JFH1 has unique replication capacity in Huh7 cells. In the same year, Lindenbach et al[64] developed the more efficient HCV 2a cell culture system (J6/JFH1) by replacing the Core-NS2 region from another 2a isolate. Recently, intergenotypic recombinants (4a/JFH1) cell culture systems were developed containing the structural genes (Core, E1, and E2), p7, and all or part of NS2 of the 4a prototype strain ED43. These Chimeric viruses allowed genotype-specific functional analyses of Core-NS2 and screening of neutralizing antibodies and inhibitors targeting this region[68].

Very recently, Gottwein et al (2011) developed reporter viruses using JFH1-based recombinants expressing core-NS2 of genotype 1 to 7 prototype isolates, Core-NS2 region of ED43 was used to generate the reporter recombinant system. Enhanced GFP (EGFP) or RLuc was inserted into C-terminal domain III of JFH1 NS5A at a site described previously by Moradpour et al 2004 (downstream of aa 2356 or 2390, numbering with reference to H77, Genotype 1b). These reporter viruses can be used for high-throughput fluorescence- and luminescence-based genotype-specific functional studies of HCV-receptor interactions, serum-neutralizing antibodies and therapeutics interfering with HCV entry or assembly.


Chimpanzees are the only model for studying HCV infection mirroring immuno-pathogenesis and viral persistence observed in human infections. Chimpanzees can be infected with intravenous inoculation of HCV particles and by intrahepatic transfection with RNA transcripts from full-length HCV cDNA clones. Molecular infectious clones of genotypes 1a (strains H77, HCV-1, HC-TN), 1b (HC-J4, Con1, HCV-N), and 2a (HC-J6 and JFH1) were used to initiate monoclonal infections in chimpanzees (reviewed in Gottwein et al[69]), in order to study the function of certain genome regions by reverse genetic studies, and to study HCV natural history and protective immunity. Furthermore, plasma pools from monoclonally infected chimpanzees were used for virus challenge in vaccine studies and antivirals in chimpanzees[70] or SCID-uPA mice engrafted with human hepatocytes[71]. In 2010, Gottwein and Scheel et al generated consensus cDNA clones of strains ED43 (genotype 4a) which were fully functional in chimpanzees[70]. With the develpoment of HCV genotype 4 chimpanzee model, it was possible to analyze certain viral genome regions by reverse genetics, host immune responses during the acute infection, including peripheral and intrahepatic T-cell responses, vaccines and antiviral studies particular for this important viral genotype.


Human hepatocytes were transplanted into uPA/scid mice; a transgenic mice in which the urokinase gene is driven by the human albumin promoter/enhancer, these human transplanted cells proliferated and replaced the apoptotic mice liver cells[72]. These chimeric mice were shown to be susceptible to HCV infection. Replication levels of the virus is proportional to the repopulation index of humanized cells[73]. Successful viral replication is achieved in these chimeric mice for HCV genotype 2a[74], 1a[75], 1b[76], and JFH1 intergenotypic chimeric viruses[74]. In the recently developed modified form of chimeric mice (Fah–/–Rag2–/–Il2rg–/– mouse) HCV is shown to persist for more than half a year and most likely does not have any impact on the animal’s health. HCV can also be passaged from one chimeric mouse to another with viral titers and dynamics similar to those achieved with inoculation with patient serum. These chimeric animals was used to test the antiviral drugs like interferons[74].


Treatment of HCV with pegylated interferon (PEG-IFN) and ribavirin (RBV) is becoming the standard of care (SOC) for the management of most of HCV genotypes where dual therapy is the state of the art only for non-genotype 1 infections[77]. However, several factors affect the efficacy of the PEG-INF/RBV combination regimens. Similar to the variation of treatment efficacy by viral genotype, the predictors of sustained virologic response (SVR) varies by genotype. The comparatively high cost of treatment with PEG-IFN/RBV combination regimens and the cruel side effects strengthen the importance of evaluation and optimization of the factors affecting the treatment before its initiation. Up to date, little is known about factors affecting PEG-INF/RBV treatment outcome in HCV-4. Some of these factors are virus related and others are host related factors. Virus-related factors are HCV genotype, baseline viral load and HCV quasispecies[78]. The host-related factors are single nucleotide polymorphisms (SNPs) in interleukin (IL)-28B and NS5A genes, pretreatment serum anti-E1E2 and interferon-gamma-inducible protein-10 kDa (IP-10 or CXCL10), ethnicity and liver histopathology.


HCV-4 is a difficult-to-treat genotype[78]. Moreover, high baseline viral load increases the resistance to therapy. Cut-off value of 400,000 IU/mL is used in most studies[79,80]. Another major cause of the treatment difficulty is the presence of multiple HCV-4 species[81]. The species diversity allows the virus to escape from the antiviral therapy.


A recent cohort study detects an association of the IL-28B polymorphism and the response to interferon treatment[82]. This study included 129 HCV-4 patients from three tertiary healthcare centers in Saudi Arabia. In these patients, five Single nucleotide polymorphisms (SNPs) were identified and correlated with SVR. These data showed that the IL-28B rs12979860 CC genotype and rs12980275AA were associated with SVR. Moreover, IFN/RBV resistance-determining region (IRRDR) was identified as a new region located near the C terminus of NS5A gene. SNPs in this region showed correlation with PEG-IFN/RBV treatment outcome in both HCV-2a and -2b infections. Recently, polymorphisms in this region showed a correlation with PEG-IFN/RBV treatment outcome in HCV-4 infected Egyptian patients[83].

A recent report by Shaker et al, from Egypt showed that SNPs in IL-28B (rs8099917 T/G and rs12979860 C/T) and the serum levels of IL-10 and IL-28 may be promising predictors for HCV genotype 4 pegylated interferon/ribavirin-therapy outcome[84]. A recently published meta analysis regarding the implications of IL-28B polymorphisms (rs12979860 and rs8099917) in spontaneous and treatment-related clearance for patients with hepatitis C showed that these polymorphisms have strong predictive association of therapy response for HCV genotype 4[85]. Fortunato et al (2008)[86] reported that genetic variants in the IRF-1 and Stat1 genes of the IFN pathway are also associated with HCV infection.

Pretreatment serum anti-E1E2 and IP-10 are also other factors affecting the treatment response. Pretreatment serum anti-E1E2 response predicts better HCV RNA clearance and treatment outcome. The combination of anti-E1E2 and IP-10 significantly improves the prediction of treatment response. This warrants further investigation and validation on larger cohorts of patients in the context of new therapeutic strategies. Data on the correlation between ethnicity and PEG-IFN/RBV treatment outcome on HCV-4 patients are still controversial. Two studies evaluated the effect of ethnicity between Egyptians and Europeans on the therapeutic outcome of PEG-IFN/RBV treatment and showed no significant difference between the two different ethnic groups[87,88]. On the contrary, recent study concluded that Egyptian ethnicity is a favorable factor for clinical outcome[77,89]. In Egypt, a study concluded that severe fibrosis, severe steatosis, treatment with standard interferon are predictors of low SVR[90]. This study suggests that the routine assessment of factors predictive of a treatment response should consider pretreatment serum alpha fetoprotein (AFP) level.

Currently, hepatitis C patients are treated with interferon alpha (IFN-a) given either alone or in combination with the nucleoside analog ribavirin. IFN system is reported to mediate antiviral, antiproliferative, immune, and other cellular effects[91]. A hallmark of all IFNs is their ability to enhance the expression of numerous genes. Some of these genes encode effector proteins like PKR protein with remarkable antiviral activities. In humans, IFN antiviral action is mediated by the induction of at least two major proteins, protein kinase R, and MxA[92]. PKR (protein kinase RNA-regulated) is involved in the pathogenesis of HCV genotype 4 related HCC by inhibiting viral and cellular proteins related to cell growth and proliferation. PKR gene expression is considered a reliable marker to predict HCC with high sensitivity, specificity and diagnostic accuracy[93].


The development of a protective vaccine against HCV has proven to be an extremely challenging task. Extensive research in this area suggests that a successful HCV vaccine will need to stimulate the production of neutralizing antibodies (perhaps against E1 and or E2 HCV envelope glycoproteins) and potent HCV-specific T cell responses.

E1 and E2 proteins are present on the surface of viral particles and thus are recognized by neutralizing antibodies. E2 glycoprotein is considered the major target of HCV neutralizing antibodies, and it is also the HCV receptor-binding protein, which has been shown to interact with CD81 tetraspanin and scavenger receptor BI (SRB1), two HCV co-receptors.

Most of the antibodies identified to date target receptor-binding epitopes within E2 glycoprotein. Targeting host factors may represent an alternative approach to preventing HCV entry. These antibodies do not target the virus particle itself, but rather block viral-host receptor interaction. Indeed a number of anti-receptor antibodies targeting CD81 and SR-BI have been shown to block viral entry.


Identification of mechanisms of immune protection is a crucial step in HCV vaccine design. Indeed, the identification of human antibody clones with broad neutralizing activity is important for the design of an effective vaccine against most known human viruses. It has been shown before that induction of neutralizing antibodies following vaccination comprise a major component of protection, provided by adaptive immune response, against a number of viruses. However, in the case of hepatitis C virus, the infection can persist even in the presence of a broadly neutralizing antibody in over 50% of cases, where many patients fail to clear the virus and instead develop chronic infection in the presence of HCV neutralizing antibodies which are usually detectable within 1-3 months of HCV infection. This can result in various forms of chronic hepatitis, liver cirrhosis and can eventually lead to hepatocellular carcinoma and death. Various mechanisms underlying this phenomenon have been suggested, and one of the most recently proposed ones is the presence of interfering antibodies that stops antibody neutralization responses. It has been reported before that the majority of chronically infected patients display cross-reactive neutralizing antibodies in their serum. Neutralizing antibodies have not been detected in several cases of acute resolving infections, and the detection of neutralizing antibodies in acutely infected individuals did not seem to be associated with viral clearance. On the contrary, another study reported that some patients had a progressive emergence of a relatively strong neutralizing response in correlation with a decrease in viral load in blood. Inline with this study, it has been also demonstrated that neutralizing antibodies with high-titer serum were detected in individuals resolving infection. Furthermore, most individuals progressing to chronic infection showed low-titer neutralizing antibodies during early acute infection where virus escape might have occurred. Together, these observations suggest the clinical importance of neutrlalizing antibodies.


HCV E1 glycoprotein displays a relatively high degree of conservation than E2. It has been proven to be a difficult target for monoclonal antibody neutralization. This can be explained on the basis of its proposed low immunogenicity comparable to E2 protein[94,95]. Despite this challenge, two monoclonal antibodies directed against HCV glycoprotein E1 were identified (IGH 505, and IGH 526)[96]. These antibodies strongly neutralize HCVpp bearing E1 envelope glycoprotein of different genotypes such as 1a, 2a, 1b, 4a, 5a, and 6a, whereas they failed to neutralize HCV genotype 3a. The epitopes for both monoclonal antibodies were mapped to the region encompassing amino acids 313 to 327. However, the mechanism by which these E1-directed monoclonal antibodies neutralize HCV infection remains unclear[96]. In addition to these two antibodies, H-111 antibody was reported to react in ELISA with expressed E1 proteins from genotypes 1a, 1b, 2b, and 3a. H-111 was reported to bind to 192YEVRNVSGVYH211 region of E1. Furthermore, another identified E1 epitopic region was considered as universally conserved region of E1 comprising aminoacids 315-328.

E2 encodes clusters of highly immunogenic overlapping epitopes. An epitope involved in HCV virus neutralization located within the HCV E2 protein and comprising amino acids 412-419 have been previously identified. Another main target of neutralizing antibodies is the hypervariable region (HVR1) in the HCV E2 envelope protein[97]. The apparent variability of E2 hypervariable region (HVR1), the first 27 amino acids of the E2 ectodomain, seems to be driven by antibody selection of immune-escape variants. Despite the sequence variability of HVR1, the physicochemical properties of the residues at each position and the conformation of HVR1 are highly conserved among various species. E2 HVR1 is also reported to be responsible for virus binding and entry. It has been proposed that HVR1 plays the role of a neutralizing epitope since this region shows marked sequence variability. It has also been reported before that resolved infection is associated with stable HVR1 sequences, whereas persistent HCV infection is associated by HVR1 sequence change. Altogether, this suggests that HVR1 is playing an important role in targeting the antibody response to HCV E2 glycoprotein. Unfortunately, HVR1 immunogenic epitopes tend to be isolate specific with no recognition for other genotypes, leading to viral escape. Several HCV escape mutants were reported in the literature, among these is the Q412H was reported in chronic HCV carriers. Recently, it has been shown that the sequences of E1 and E2 glycoproteins are driven by neutralizing antibody responses where escape mutant strains shortly become the dominant ones.


HCV is often initialy diagnosed in a late stage when the therapeutic options are already limited. Due to slow and silent onset, many patients are unaware of their infection and about 50% of cases remain undetected[98]. In particular, HCV has been given increasing attention because of its wide and deep penetration in the community, coupled with a very high incidence of HCC in chonic HCV infected patients. Indeed, hepatocellular carcinoma (HCC) has become the major cause of death in individuals persistently infected with HCV[99]). Once liver cirrhosis is established in hosts infected with HCV, HCC develops at a yearly rate of about 6%[91]). HCC accounts for about 2% of total cancers, and is the most lethal form of cancer, and its incidence has been rising over the last 30 years[1,100]. In line with these reports, an indian study found that HCV infection (genotype 4) increases the risk of developing HCC by three folds compared to other genotypes[101]. On the contrary, in Egypt, where HCV genotype 4 predominates, it was reported that there is no association between infection with genotype 4 and the development of HCC[102].


The mechanism of carcinogenesis is not fully understood. Some studies demonstrate that when inflammation is induced in the liver in the presence of HCV core protein, the production of oxidative stress is triggered to an extent that cannot be stopped by a normal physiological antagonistic agent[103]. Moreover, Hepatic steatosis, a common and serious feature of hepatitis C virus (HCV) infection, may enhance oxidative stress overproduction[104]. Other possible pathways involving HCV viral core protein would be the alteration of the expression of some cellular genes and modulation of intracellular signaling pathways. For an example, tumor necrosis factor (TNF)-α and interleukin-1 β have been found to be transcriptionally activated at the protein and mRNA levels in HCV infected mice[105]. Furthermore, it has been reported before that liver disease progression from chronic liver disease to HCC due to HCV genotype 4 infection is associated with an imbalance between certain types of cytokines[106]. In addition to these causes, the HCV core protein was reported to modulate the intracellular signaling pathways of some proteins such as retinoid X receptor (RXR)-α, which play essential roles in cell proliferation and metabolism[107].


There are no conflicts of interest with regard to the present study.


1 Baldo V, Baldovin T, Trivello R, Floreani A. Epidemiology of HCV infection. Curr Pharm Des 2008 14: 1646-1654

2 Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533-543

3 Miller FD, Abu-Raddad LJ. Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt. Proc Natl Acad Sci U S A 2009; 107: 14757-14762

4 Mahboobi N, Porter SR, Karayiannis P, Alavian SM. Dental treatment as a risk factor for hepatitis B and C viral infection. A review of the recent literature. J Gastrointestin Liver Dis 2013; 22: 79-86

5 Gentile I, Di Flumeri G, Scarica S, Frangiosa A, Foggia M, Reynaud L, Borgia G. Acute hepatitis C in patients undergoing hemodialysis: experience with high-dose interferon therapy. Minerva Urol Nefrol 2013; 65: 83-84

6 Guadagnino V, Stroffolini T, Caroleo B, Menniti Ippolito F, Rapicetta M, Ciccaglione AR, Chionne P, Madonna E, Costantino A, De Sarro G et al. Hepatitis C virus infection in an endemic area of Southern Italy 14 years later: evidence for a vanishing infection. Dig Liver Dis 2013; 45 403-407

7 Kim JY, Cho J, Hwang SH, Kil H, Bae SH, Kim YS, Lee HC, Jeong SH Behavioral and healthcare-associated risk factors for chronic hepatitis C virus infection in Korea. J Korean Med Sci 2012; 27 1371-1377

8 Weinbaum C, Lyerla R, Margolis HS. Prevention and control of infections with hepatitis viruses in correctional settings. Centers for Disease Control and Prevention. MMWR Recomm Rep 2003; 52 1-36; quiz CE31-34

9 Gurtsevitch VE. Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis. Biochemistry (Mosc) 2008; 73: 504-513

10 Pestova TV, Kolupaeva VG, Lomakin IB, Pilipenko EV, Shatsky IN, Agol VI and Hellen CU. Molecular mechanisms of translation initiation in eukaryotes. Proc Natl Acad Sci U S A 2001; 98: 7029-7036

11 Otto GA, Puglisi JD. The pathway of HCV IRES-mediated translation initiation. Cell 2004; 119: 369-380

12 Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol 2007; 5: 453-463

13 Goffard A, Dubuisson J. Glycosylation of hepatitis C virus envelope proteins. Biochimie 2003; 85: 295-301

14 Deleersnyder V, Pillez A, Wychowski C, Blight K, Xu J, Hahn YS, Rice CM, Dubuisson J. Formation of native hepatitis C virus glycoprotein complexes. J Virol 1997; 71: 697-704

15 Vieyres G, Thomas X, Descamps V, Duverlie G, Patel AH, Dubuisson J Characterization of the envelope glycoproteins associated with infectious hepatitis C virus 2010; J Virol 84: 10159-10168

16 Kuiken C, Simmonds P. Nomenclature and numbering of the hepatitis C virus. Methods Mol Biol 2009; 510: 33-53

17 Murphy DG, Willems B, Deschenes M, Hilzenrat N, Mousseau R, Sabbah S. Use of sequence analysis of the NS5B region for routine genotyping of hepatitis C virus with reference to C/E1 and 5’ untranslated region sequences. J Clin Microbiol 2007; 45: 1102-1112

18 Wu S, Kanda T, Nakamoto S, Jiang X, Miyamura T, Nakatani SM, Ono SK, Takahashi-Nakaguchi A, Gonoi T, Yokosuka O. Prevalence of hepatitis C virus subgenotypes 1a and 1b in Japanese patients: ultra-deep sequencing analysis of HCV NS5B genotype-specific region. PLoS One, 8, e73615

19 Negro F, Alberti A. The global health burden of hepatitis C virus infection Liver Int 2011; 31: Suppl 2, 1-3

20 Zhao L, Feng Y, Xia XS. The different epidemic and evolution of HCV genotypes. Yi Chuan 2012; 34: 666-672

21 Liberto MC, Marascio N, Zicca E, Matera G. Epidemiological features and specificities of HCV infection: a hospital-based cohort study in a university medical center of Calabria region. BMC Infect Dis 2012; 12: Suppl 2, S4.

22 Panasiuk A, Flisiak R, Mozer-Lisewska I, Adamek A, Tyczyno M, Halota W, Pawłowska M, Stańczak J, Berak H, Wawrzynowicz-Syczewska M, Boroń-Kaczmarska A, Łapiński TW, Grzeszczuk A, Piekarska A, Tomasiewicz K, Jabłkowski M, Kryczka W, Zarebska-Michaluk D, Stepień P, Garlicki AM, Kozłowska J, Wiercińska-Drapało A, Zasik E, Mazur W, Dobracka B, Dobracki W, Simon K, Ryzko J, Pawłowska J, Dzierzanowska-Fangrat K, Januszkiewicz-Lewandowska D, Szenborn L, Zaleska I, Rokitka M, Strawińska E, Balinowska K, Smiatacz T, Stalke P, Sikorska K, Lakomy A, Zdrojewski M, Lachowicz A. Distribution of HCV genotypes in Poland. Przegl Epidemiol 2013; 67, 11-16, 99-103

23 Afzal MS, Anjum S, Zaidi NU. Effect of Functional Interleukin-10 Polymorphism on Pegylated Interferon-alpha Plus Ribavirin Therapy Response in Chronic Hepatitis C Virus Patients Infected With 3a Genotype in Pakistani Population.Hepat Mon 2014; 13: e10274

24 Anjum S, Ali S, Ahmad T, Afzal MS, Waheed Y, Shafi T, Ashraf M, Andleeb S. Sequence and structural analysis of 3’ untranslated region of hepatitis C virus, genotype 3a, from pakistani isolates. Hepat Mon 2013; 13: e8390

25 Waheed Y, Saeed U, Anjum S, Afzal MS, Ashraf M. Development of Global Consensus Sequence and Analysis of Highly Conserved Domains of the HCV NS5B Prote in. Hepat Mon 2012; 12: e6142

26 Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, Amarapurkar D, Chen CH, Dou X, El Khayat H, Elshazly M, Esmat G, Guan R, Han KH, Koike K, Largen A, McCaughan G, Mogawer S, Monis A, Nawaz A, Piratvisuth T, Sanai FM, Sharara AI, Sibbel S, Sood A, Suh DJ, Wallace C, Young K, Negro F. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011; 31: Suppl 2, 61-80

27 Ray R, Meyer K, Banerjee A, Basu A, Coates S, Abrignani S, Houghton M, Frey SE, Belshe RB. Characterization of antibodies induced by vaccination with hepatitis C virus envelope glycoproteins. J Infect Dis 2010; 202: 862-866

28 Tokita H, Shrestha SM, Okamoto H, Sakamoto M, Horikita M, Iizuka H, Shrestha S, Miyakawa Y, Mayumi M. Hepatitis C virus variants from Nepal with novel genotypes and their classification into the third major group. J Gen Virol 1994; 75 ( Pt 4): 931-936

29 Tokita H, Okamoto H, Iizuka H, Kishimoto J, Tsuda F, Lesmana LA, Miyakawa Y, Mayumi M. Hepatitis C virus variants from Jakarta, Indonesia classifiable into novel genotypes in the second (2e and 2f), tenth (10a) and eleventh (11a) genetic groups. J Gen Virol 1996; 77 ( Pt 2 ): 293-301

30 Andre P, Komurian-Pradel F, Deforges S, Perret M, Berland JL, Sodoyer M, Pol S, Brechot C, Paranhos-Baccala G, Lotteau V. Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA- Containing Particles. J Virol 2002; 76: 6919-6928

31 Nielsen SU, Bassendine MF, Burt AD, Martin C, Pumeechockchai W, Toms GL. Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients. J Virol 2006; 80: 2418-2428

32 Bartosch B, Bukh J, Meunier JC, Granier C, Engle RE, Blackwelder WC, Emerson SU, Cosset FL, Purcell RH. In vitro assay for neutralizing antibody to hepatitis C virus: evidence for broadly conserved neutralization epitopes. Proc Natl Acad Sci U S A 2003; 100: 14199-14204

33 Bartosch B, Cosset FL. Cell entry of hepatitis C virus. Virology 2006; 348: 1-12

34 Bartenschlager R. The hepatitis C virus replicon system: from basic research to clinical application. J Hepatol 2005; 43: 210-216

35 Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Complete Replication of Hepatitis C Virus in Cell Culture. Science 2005; 309: 623-626

36 Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Kräusslich HG, Mizokami M, Bartenschlager R, Liang TJ. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005; 11: 791-796

37 Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A 2005; 102: 9294-9299

38 Bhattacherjee V, Prescott LE, Pike I, Rodgers B, Bell H, El-Zayadi AR, Kew MC, Conradie J, Lin CK, Marsden H et al. Use of NS-4 peptides to identify type specific antibody to hepatitis C virus genotypes 1, 2, 3, 4, 5 and 6. J Gen Virol 1995; 76 ( Pt 7): 1737-1748

39 Rapicetta M, Argentini C, Dettori S, Spada E, Pellizzer G, Gandin C. Molecular heterogeneity and new subtypes of HCV genotype 4. Res Virol 1998; 149: 293-297

40 Simmonds P, Holmes EC, Cha TA, Chan SW, McOmish F, Irvine B, Beall E, Yap PL, Kolberg J, Urdea MS. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol 1993; 74 ( Pt 11): 2391-2399

41 Simmonds P, McOmish F, Yap PL, Chan SW, Lin CK, Dusheiko G, Saeed AA, Holmes EC. Sequence variability in the 5’ non-coding region of hepatitis C virus: identification of a new virus type and restrictions on sequence diversity. J Gen Virol 1993; 74 ( Pt 4): 661-668

42 Chamberlain RW, Adams N, Saeed AA, Simmonds P, Elliott RM. Complete nucleotide sequence of a type 4 hepatitis C virus variant, the predominant genotype in the Middle East. J Gen Virol 1997; 78 ( Pt 6): 1341-1347

43 Timm J, Neukamm M, Kuntzen T, Kim AY, Chung RT, Brander C, Lauer GM, Walker BD, Allen TM. Characterization of full-length hepatitis C virus genotype 4 sequences. J Viral Hepat 2007; 14: 330-337

44 Lohmann V, Korner F, Koch J, Herian U, Theilmann L. Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999; 285: 110-113

45 Blight KJ, McKeating JA, Marcotrigiano J, Rice CM. Efficient replication of hepatitis C virus genotype 1a RNAs in cell culture. J Virol 2003; 77: 3181-3190

46 Grobler JA, Markel EJ, Fay JF, Graham DJ, Simcoe AL, Ludmerer SW, Murray, EM, Migliaccio G, Flores OA. Identification of a key determinant of hepatitis C virus cell culture adaptation in domain II of NS3 helicase. J Biol Chem 2003; 278: 16741-16746

47 Tscherne DM, Jones CT, Evans MJ, Lindenbach BD, McKeating JA, Rice CM. Time- and temperature-dependent activation of hepatitis C virus for low-pH triggered entry. J Virol 2006; 80: 1734-1741

48 Abe K, Ikeda M, Dansako H, Naka K, Kato N. Cell culture-adaptive NS3 mutations required for the robust replication of genome-length hepatitis C virus RNA. Virus Res 2007; 125: 88-97

49 Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science 2000; 290: 1972-1974

50 Guo JT, Bichko VV, Seeger C. Effect of alpha interferon on the hepatitis C virus replicon. J Virol 2001; 75: 8516-8523

51 Ikeda M, Yi M, Li K, Lemon SM. Selectable subgenomic and genome length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells. J Virol 2002; 76, 2997-3006.

52 Kato T, Date T, Miyamoto M, Furusaka A, Tokushige K, Mizokami M, Wakita T. Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterology 2003; 125: 1808-1817

53 Krieger N, Lohmann V,Bartenschlager R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J Virol 2001; 75: 4614-4624

54 Maekawa S, Enomoto N, Sakamoto N, Kurosaki M, Ueda E, Kohashi T, Watanabe H, Chen CH, Yamashiro T, Tanabe Y, Kanazawa N, Nakagawa M, Sato C, Watanabe M. Introduction of NS5A mutations enables subgenomic HCV replicon derived from chimpanzee-infectious HC-J4 isolate to replicate efficiently in Huh-7 cells. J Viral Hepat 2004; 11: 394-403

55 Mori K, Abe K, Dansako H, Ariumi Y, Ikeda M, Kato N. New efficient replication system with hepatitis C virus genome derived from a patient with acute hepatitis C. Biochem Biophys Res Commun 2008; 371: 104-109

56 Yi M, Bodola F, Lemon SM. Subgenomic hepatitis C virus replicons inducing expression of a secreted enzymatic reporter protein. Virology 2002; 304: 197-210

57 Saeed M, Scheel TK, Gottwein JM, Marukian S, Dustin LB, Bukh J, Rice CM. Efficient replication of genotype 3a and 4a hepatitis C virus replicons in human hepatoma cells. Antimicrob Agents Chemother 2012; 56: 5365-5373

58 Bartosch B, Dubuisson J, Cosset FL. Infectious hepatitis C virus pseudo particles containing functional E1-E2 envelope protein complexes. J Exp Med 2003; 197: 633-642

59 Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM, McKeating JA. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of seudotyped retroviral particles. Proc Natl Acad Sci U S A 2003; 100: 7271-7276

60 Lavillette D, Tarr AW, Voisset C, Donot P, Bartosch B, Bain C, Patel AH,Dubuisson J, Ball JK, Cosset FL. Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus. Hepatology 2005; 41: 265-274

61 McKeating JA, Zhang LQ, Logvinoff C, Flint M, Zhang J, Yu J, Butera D, Ho DD, Dustin LB, Rice CM, Balfe P. Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner. J Virol 2004; 78: 8496-8505

62 Meunier JC, Engle RE, Faulk K, Zhao M, Bartosch B, Alter H, Emerson SU, Cosset FL, Purcell RH, Bukh J. Evidence for cross-genotype neutralization of hepatitis C virus pseudo-particles and enhancement of infectivity by apolipoprotein C1. Proc Natl Acad Sci U S A 2005; 102: 4560-4565

63 Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465: 96-100

64 Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Complete replication of hepatitis C virus in cell culture. Science 2005; 309: 623-626

65 Scheel TK, Gottwein JM, Mikkelsen LS, Jensen TB, Bukh J. Recombinant HCV variants with NS5A from genotypes 1-7 have different sensitivities to an NS5A inhibitor but not interferon-alpha. Gastroenterology 2011; 140: 1032-1042

66 Imhof I, Simmonds P. Development of an intergenotypic hepatitis C virus (HCV) cell culture method to assess antiviral susceptibilities and resistance development of HCV NS3 protease genes from HCV genotypes 1 to 6. J Virol 2010; 84: 4597-4610.

67 Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Kräusslich HG, Mizokami M, Bartenschlager R, Liang TJ. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005; 11: 791-796.

68 Scheel TK, Gottwein JM, Jensen TB, Prentoe JC, Hoegh AM, Alter HJ, Eugen, Olsen J, Bukh J. Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization. Proc Natl Acad Sci U S A 2008; 105: 997-1002

69 Gottwein JM, Jensen TB, Mathiesen CK, Meuleman P, Serre SB, Lademann JB, Ghanem L, Scheel TK, Leroux-Roels G, Bukh J. Development and application of hepatitis C reporter viruses with genotype 1 to 7 core-nonstructural protein 2 (NS2) expressing fluorescent proteins or luciferase in modified JFH1 NS5A. J Virol 2011; 85: 8913-8928

70 Bowen DG, Walker CM. Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. J Exp Med 2005; 201: 1709-1714

71 Meuleman P, Libbrecht L, De Vos R, de Hemptinne B, Gevaert K, Vandekerckhove J, Roskams T and Leroux-Roels G. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology 2005; 41: 847-856

72 Rhim JA, Sandgren EP, Palmiter RD, Brinster RL. Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc Natl Acad Sci U S A 1995 92: 4942-4946

73 Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A, Addison WR, Fischer KP, Churchill TA, Lakey JR, Tyrrell DL, Kneteman NM. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 2001; 7: 927-933

74 Bissig KD, Wieland SF, Tran P, Isogawa M, Le TT, Chisari FV, Verma IM. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest 2010; 120: 924-930

75 Hiraga N, Imamura M, Tsuge M, Noguchi C, Takahashi S, Iwao E, Fujimoto Y, Abe H, Maekawa T, Ochi H, Tateno C, Yoshizato K, Sakai A, Sakai Y, Honda M, Kaneko S, Wakita T, Chayama K. Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon. FEBS Lett 2007; 581: 1983-1987

76 Kimura T, Imamura M, Hiraga N, Hatakeyama T, Miki D, Noguchi C, Mori N, Tsuge M, Takahashi S, Fujimoto Y, Iwao E, Ochi H, Abe H, Maekawa T, Arataki K, Tateno C, Yoshizato K, Wakita T, Okamoto T, Matsuura Y, Chayama K. Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice. J Gen Virol 2008; 89: 2108-2113

77 Moucari R, Ripault MP, Martinot-Peignoux M, Voitot H, Cardoso AC, Stern C, Boyer N, Maylin S, Nicolas-Chanoine MH, Vidaud M, Valla D, Bedossa P, Marcellin P. Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4. Gut 2009; 58: 1662-1669

78 Esmat G, El Kassas M, Hassany M, Gamil ME, El Raziky M. How to optimizeHCV therapy in genotype 4 patients. Liver Int 2013; 33 Suppl 1: 41-45

79 Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Muhammadi M, Sayed K, Moustafa A, Hakem SA, Ibrahiem A, Moniem M, Mansour H, Abdelaziz M. Pegylated interferon alpha 2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response. Hepatology 2007; 46: 1732-1740

80 Salomon JA, Weinstein MC, Hammitt JK and Goldie SJ. Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population. JAMA 2003; 290: 228-237

81 Fan X, Mao Q, Zhou D, Lu Y, Xing J, Xu Y, Ray SC, Di Bisceglie AM. High diversity of hepatitis C viral quasispecies is associated with early virological response in patients undergoing antiviral therapy. Hepatology 2009; 50: 1765-1772

82 Abdo AA, Al-Ahdal MN, Khalid SS, Helmy A, Sanai FM, Alswat K, Al-Hamoudi W, Ali SM, Al-Ashgar HI, Al-Mdani A et al. IL28B polymorphisms predict the virological response to standard therapy in patients with chronic hepatitis C virus genotype 4 infection. Hepatol Int 2013; 7: 533-538

83 El-Shamy A, Shoji I, El-Akel W, Bilasy SE, Deng L, El-Raziky M, Jiang DP, Esmat G, Hotta H. NS5A sequence heterogeneity of hepatitis C virus genotype 4a predicts clinical outcome of pegylated-interferon-ribavirin therapy in Egyptian patients. J Clin Microbiol 2012; 50: 3886-3892

84 Shaker OG, Sadik NA. Polymorphisms in interleukin-10 and interleukin-28B genes in Egyptian patients with chronic hepatitis C virus genotype 4 and their effect on the response to pegylated interferon/ribavirin-therapy. J Gastroenterol Hepatol, 2012; 27: 1842-1849

85 Jimenez-Sousa MA, Fernandez-Rodriguez A, Guzman-Fulgencio M, Garcia-Alvarez M, Resino S. Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C. BMC Med 2013; 11: 6.

86 Fortunato G, Calcagno G, Bresciamorra V, Salvatore E, Filla A, Capone S, Liguori R, Borelli S, Gentile I, Borrelli F, Borgia G, Sacchetti L. Multiple sclerosis and hepatitis C virus infection are associated with single nucleotide polymorphisms in interferon pathway genes. J Interferon Cytokine Res 2008; 28: 141-152

87 Papastergiou V, Dimitroulopoulos D, Skorda L, Lisgos P, Ketikoglou I, Kostas N, Karatapanis S. Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: does ethnicity matter? J Med Virol 2012; 84: 1217-1223

88 Dimitroulopoulos D, Elefsiniotis I, Pavlidis C, Xinopoulos D, Tsamakidis K, Patsavela S, Kypreos D, Ferderigou A, Korkolis D, Koutsounas S et al. European vs. Egyptian HCV-4 patients with elevated baseline HCV RNA, treated with PEG-IFN-alpha2a and ribavirin: the role of rapid and early virologic response. Hepat Mon 10: 193-198

89 Roulot D, Bourcier V, Grando V, Deny P, Baazia Y, Fontaine H, Bailly F, Castera L, De Ledinghen V, Marcellin P, Poupon R, Bourlière M, Zarski JP, Roudot-Thoraval F; Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection. J Viral Hepat 2007; 14: 460-467

90 Gad RR, Males S, El Makhzangy H, Shouman S, Hasan A, Attala M, El Hoseiny M, Zalata K, Abdel-Hamid M, Fontanet A, Mohamed MK, Esmat G. Predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C. Liver Int 2008; 28: 1112-1119

91 Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, Kumada H. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol 1998; 28: 930-938

92 Haller O, Frese M, Kochs G. Mx proteins: mediators of innate resistance to RNA viruses. Rev Sci Tech 1998; 17: 220-230

93 Mohamed AA, Nada OH, El Desouky MA. Implication of protein kinase R gene quantification in hepatitis C virus genotype 4 induced hepatocarcinogenesis. Diagn Pathol 2012; 7: 103

94 Pietschmann T, Kaul A, Koutsoudakis G, Shavinskaya A, Kallis S, Steinmann E, Abid K, Negro F, Dreux M, Cosset FL, Bartenschlager R. Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. Proc Natl Acad Sci U S A 2006; 103: 7408-7413

95 Dreux M, Pietschmann T, Granier C, Voisset C, Ricard-Blum S, Mangeot PE, Keck Z, Foung S, Vu-Dac N, Dubuisson J, Bartenschlager R, Lavillette D, Cosset FL. High density lipoprotein inhibits hepatitis C virus-neutralizing antibodies by stimulating cell entry via activation of the scavenger receptor BI. J Biol Chem 2006; 281: 18285-18295

96 Meunier JC, Russell RS, Goossens V, Priem S, Walter H, Depla E, Union A, Faulk KN, Bukh J, Emerson SU, Purcell RH. Isolation and characterization of broadly neutralizing human monoclonal antibodies to the e1 glycoprotein of hepatitis C virus. J Virol 2008; 82: 966-973

97 Farci P, Shimoda A, Wong D, Cabezon T, De Gioannis D, Strazzera A, Shimizu Y, Shapiro M, Alter HJ, Purcell RH. Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein. Proc Natl Acad Sci U S A 1996; 93 15394-15399

98 Khaliq S, Latief N, Jahan S. Role of different regions of the hepatitis C virus genome in the therapeutic response to interferon-based treatment. Arch Virol 2014; 159(1): 1-15

99 Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 2007; 22 Suppl 1: S108-111.

100 Abou-Alfa GK. Hepatocellular carcinoma: molecular biology and therapy. Semin Oncol 2006; 33: S79-83

101 Ryu SH, Fan X, Xu Y, Elbaz T, Zekri AR, Abdelaziz AO, Di Bisceglie AM. Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt. J Med Virol 2009; 81: 844-847

102 Sarma MP, Asim M, Medhi S, Bharathi T, Kar P. Hepatitis C virus related hepatocellular carcinoma: a case control study from India. J Med Virol 2012; 84: 1009-1017

103 Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T, Imai K, Todoroki T, Kimura S, Koike K. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001; 61: 4365-4370

104 Koike K, Moriya K. Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH. J Gastroenterol 2005; 40: 329-336

105 Tsutsumi T, Suzuki T, Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Matsuura, Y, Kimura S, Koike K, Miyamura T. Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein. Virology 2002; 304: 415-424

106 Zekri AR, Ashour MS, Hassan A, Alam El-Din HM, El-Shehaby AM, Abu Shady MA. Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression. World J Gastroenterol 2005; 11: 6624-6630

107 Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology 2002; 35: 937-946

Peer reviewers: Munachika Enjoji, MD, PhD, Health Care Center, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; Ivan Gentile, Department of Public Medicine and Social Security- Section of Infectious Diseases (Ed. 18), University of Naples “Federico II”, via S. Pansini, 5- I-80131 Naples Italy.


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.