Identification of a Naturally Occurring Recombinant Genotype 2/6 Hepatitis C Virus

Noppornpanth, Suwanna; Lien, Truong Xuan; Poovorawan, Yong; Smits, Saskia L.; Osterhaus, Albert D. M. E.; Haagmans, Bart L.

doi:10.1128/jvi.00312-06

Cited by 131 publications

(108 citation statements)

References 58 publications

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“…The ED43/JFH1-␤ and -␥ recombinants with junctions inside NS2 and at the NS2/NS3 cleavage site, respectively, were viable. Interestingly, naturally occurring intergenotypic recombinant isolates with the same 3Ј-terminal junctions as used in the ␤-and ␥-but not in the ␣-construct have been described (13,19). A study on JFH1-based inter-and intragenotypic recombinants suggested that the ␣-junction (termed C3), located in the N terminus of NS2, in general was favorable in obtaining the most efficient phenotype (9).…”

Section: Discussionmentioning

confidence: 99%

Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization

Scheel¹,

Gottwein²,

Jensen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

170

250

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Efficient in vitro systems to study the life cycle of hepatitis C virus (HCV) were recently developed for JFH1 (genotype 2a), which has unique replication capacity in Huh7 cells. We developed 4a/JFH1 intergenotypic recombinants containing the structural genes (Core, E1, and E2), p7, and all or part of NS2 of the 4a prototype strain ED43 that, after transfection of Huh7.5 cells with RNA transcripts, produced infectious viruses. Compared with the J6/JFH control virus, production of viruses was delayed. However, efficient spread of infection and high HCV RNA and infectivity titers were obtained in serial passages. Sequence analysis of recovered viruses and subsequent reverse genetic studies revealed a vital dependence on one or two NS2 mutations, depending on the 4a/2a junction. Infectivity of ED43/JFH1 viruses was CD81 dependent. The genotype 4 cell culture systems permit functional analyses as well as drug and vaccine research on an increasingly important genotype in the Middle East, Africa, and Europe. We also developed genotype 1a intergenotypic recombinants from H77C with vital mutations in NS3. Using H77C/JFH1 and ED43/JFH1 viruses, we demonstrated high homologous neutralizing antibody titers in 1a and 4a patient sera, respectively. Furthermore, availability of JFH1 viruses with envelope proteins of the six major HCV genotypes permitted cross-neutralization studies; 1a and 4a serum crossneutralized 1a, 4a, 5a, and 6a but not 2a and 3a viruses. Thus, the JFH1 intergenotypic recombinants will be of importance for future studies of HCV neutralization and accelerate the development of passive and active immunoprophylaxis.Egypt ͉ hepatitis C virus strain ED43 ͉ in vitro infection ͉ intergenotypic recombinant ͉ vaccine A pproximately 180 million people are infected with hepatitis C virus (HCV) and are at increased risk of developing severe liver disease. HCV isolates from around the world cluster into six major genotypes, which differ by Ϸ30% at the nucleotide (nt) and deduced amino acid level (1). Genotype 4 is primarily found in the Middle East and Africa (2, 3). In Egypt, Ϸ15% of the population is HCV-infected, with genotype 4a comprising Ϸ90% of cases (2, 3). This particularly high prevalence, presumably caused by an unintended transmission through parenteral treatment for schistosomiasis (3, 4), is at least partly responsible for a still rather high incidence (5), making Egypt a potential region for vaccine trials. Additionally, genotype 4 has been spreading in Europe, resulting in a prevalence of 10% in certain regions (2). Although the only approved treatment for chronic HCV infection, combination therapy with IFN-␣ and ribavirin, leads to a sustained virologic response in most of genotype 2 or 3 patients, viral clearance is obtained for only approximately half of patients with genotype 1 or 4. There is no vaccine against HCV.Research on specific antiviral drugs and vaccines has been hampered by the absence of a full viral life cycle cell culture system. However, development of such a system came with cDNA c...

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Section: Discussionmentioning

confidence: 99%

Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization

Scheel¹,

Gottwein²,

Jensen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

170

250

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“…Additionally, at least ten other different intergenotypic recombinant forms (RFs) of HCV have been described and are totally or partially characterised (Table 1). Within this group of recombinants, we can observe the presence of recombinant forms between genotypes 2 and 6 described in Vietnam [130] and Taiwan [131] , between genotypes 2 and 5 described in France [132] , between genotypes 3 and 1 in Taiwan [131] and China [133] , and between genotypes 2 and 1 reported in Japan, the United States and the Philippines [134][135][136][137] . It is interesting to note that recombinant forms found so far have a wide geographic distribution.…”

Section: Recombinationmentioning

confidence: 99%

Hepatitis C virus genetic variability and evolution

Echeverría

Moratorio

Cristina

et al. 2015

WJH

101

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Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection. Hepatitis C virus genetic variability and evolution no preventive vaccine, and though antiviral therapy has been improved in the past few years, not all patients eradicate the virus as a result of it. The main reason lies in the intrinsic genetic variability that characterises RNA viruses, such as HCV, whose RNA polymerase lacks proof-reading activity, leading to a high mutation rate and the generation of a wide range of genome variants better known as a quasispecies. Therefore this review summarises current data on HCV quasispecies dynamics, antiviral therapy and recombination events.Echeverría N, Moratorio G, Cristina J, Moreno P. Hepatitis C virus genetic variability and evolution. World J Hepatol 2015; 7(6): 831845 Available from:

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“…Currently, the global spread of HCV has accelerated with the advent of more methods and frequency of transmission routes of populations 21 which probably accounts for the appearance of pattern III HCV. However, we have found three patterns designated as II, IV, and V which may have arisen from mutation by recombination in the local population 22,23 . Mutations of the core region impact on clinical outcomes [24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

The hepatitis C virus core gene yields restriction fragments of variable length and polymorphism

Prombun¹,

Kunthalert²,

Vipsoongnern³

et al. 2015

ScienceAsia

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ABSTRACT:The hepatitis C virus (HCV) contains seven genotypes heterogeneously distributed around the world. HCV displays a high genetic diversity relevant to epidemiology, transmission, and clinical management. To explore the genetic variation of HCV in a local Thai population, we investigated the restriction fragment length polymorphism (RFLP) pattern of the core gene in 31 samples of HCV genotype 3a found in blood donors. The polymorphisms of these HCVs were clustered into five RFLP patterns (IV). Fifteen samples (48%) clustered as the RFLP pattern I and ten samples (32%) as pattern III profiles which have been previously reported. In addition, there were four samples (13%) manifest as pattern II, one sample (3%) as pattern IV, and one sample (3%) as pattern V. This study provides pointers to the molecular epidemiology of HCV genotype 3a distributed in Thailand.

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Identification of a Naturally Occurring Recombinant Genotype 2/6 Hepatitis C Virus

Cited by 131 publications

References 58 publications

Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization

Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization

Hepatitis C virus genetic variability and evolution

The hepatitis C virus core gene yields restriction fragments of variable length and polymorphism

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