Detection of hepatitis C virus natural recombinant RF1_2k/1b strain among intravenous drug users in Uzbekistan

Kurbanov, Fuat; Tanaka, Yasuhito; Avazova, Dildora; Khan, Anis; Sugauchi, Fuminaka; Кан, Н. Е.; Kurbanova-Khudayberganova, Dinara; Khikmatullaeva, Aziza; Musabaev, Erkin; Mizokami, Masashi

doi:10.1111/j.1872-034x.2007.00293.x

Cited by 48 publications

(47 citation statements)

References 27 publications

(42 reference statements)

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“…The reported recombinant was cautiously designated RF1_2k/1b, in agreement with the nomenclature used for human immunodeficiency virus (HIV) recombinants [124] . This same recombinant strain has since then been isolated in other countries, like Ireland [125] , Uzbekistan [126] , Cyprus [127] , France [128] and Estonia [129] which would suggest that, although its generation might not be favoured by natural selection, it would also not be selected against [49] . Additionally, at least ten other different intergenotypic recombinant forms (RFs) of HCV have been described and are totally or partially characterised (Table 1).…”

Section: Recombinationmentioning

confidence: 99%

“…Finally, despite recombination events between different genotypes/subtypes co-infecting the same patient are probably easier to detect, they are less likely to occur, since the strains of different subtypes differ more between them than between those from the same subtype; this would imply a lower probability of template switching and moreover, if a recombination event does indeed happen, it will likely generate recombinant sequences less viable than the parental ones. Some or even all these factors acting in concert might explain why the frequency of recombinant HCV sequences reported to date is so low [49,111,[124][125][126][127][128][129][130][131][132][133][134][135][136][137][140][141][142][143][144][145][146][147] . How relevant recombination for HCV long term evolution and its incidence in HCV infection is, has not been thoroughly investigated yet, but these findings support a potentially significant role for recombination by creating genetic variation through the reshuffling of independent variants [146] .…”

Section: Recombinationmentioning

confidence: 99%

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Hepatitis C virus genetic variability and evolution

Echeverría

Moratorio

Cristina

et al. 2015

WJH

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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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Section: Recombinationmentioning

confidence: 99%

Section: Recombinationmentioning

confidence: 99%

Hepatitis C virus genetic variability and evolution

Echeverría

Moratorio

Cristina

et al. 2015

WJH

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mentioning

confidence: 99%

“…Because of this huge genetic diversity, HCV is currently classified into six major genotypes and more than 80 subtypes (44). Recombination may be another mechanism exploited by HCV to increase genetic diversity: naturally occurring intergenotypic recombinant viruses that often have their recombination points in the trans-membrane domains of NS2 were recently identified (20,21,26,27,33,35).Recent publications have reported the presence of natural HCV subgenomic RNAs in serum and liver of infected patients, mostly containing large in-frame deletions from E1 up to NS2, always found together with the full-length wild-type (wt) RNAs (5,16,36,54). These mutant viral genomes persist for a long time (at least 2 years), and sequence analysis suggests that subgenomic (the predominant species during this period) and full-length HCV evolve independently (54).…”

mentioning

confidence: 99%

Naturally Occurring Hepatitis C Virus Subgenomic Deletion Mutants Replicate Efficiently in Huh-7 Cells and Are trans -Packaged In Vitro To Generate Infectious Defective Particles

Pacini¹,

Graziani²,

Bartholomew³

et al. 2009

J Virol

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Naturally occurring hepatitis C virus (HCV) subgenomic RNAs have been found in several HCV patients. These subgenomic deletion mutants, mostly lacking the genes encoding envelope glycoproteins, were found in both liver and serum, where their relatively high abundance suggests that they are capable of autonomous replication and can be packaged and secreted in viral particles, presumably harboring the envelope proteins from wild type virus coinfecting the same cell. We recapitulated some of these natural subgenomic deletions in the context of the isolate JFH-1 and confirmed these hypotheses in vitro. In Huh-7.5 cells, these deletioncontaining genomes show robust replication and can be efficiently trans-packaged and infect naïve Huh-7.5 cells when cotransfected with the full-length wild-type J6/JFH genome. The genome structure of these natural subgenomic deletion mutants was dissected, and the maintenance of both core and NS2 regions was proven to be significant for efficient replication and trans-packaging. To further explore the requirements needed to achieve trans-complementation, we provided different combinations of structural proteins in trans. Optimal trans-complementation was obtained when fragments of the polyprotein encompassing core to p7 or E1 to NS2 were expressed. Finally, we generated a stable helper cell line, constitutively expressing the structural proteins from core to p7, which efficiently supports trans-complementation of a subgenomic deletion encompassing amino acids 284 to 732. This cell line can produce and be infected by defective particles, thus representing a powerful tool to investigate the life cycle and relevance of natural HCV subgenomic deletion mutants in vivo.Hepatitis C virus (HCV) is an enveloped virus belonging to the family Flaviviridae. The virus genome is a positive-stranded RNA of about 9,600 nucleotides, which contains a single open reading frame (ORF) encoding both structural (core, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins (47). Two highly conserved untranslated regions (UTRs) are found at the 5Ј and 3Ј ends, which play critical roles in both viral translation and replication (13,14,23).HCV is estimated to infect 170 million people worldwide (1, 43) and in a high percentage of individuals causes a chronic liver infection that frequently evolves into an array of diseases, including cirrhosis (12, 15, 38) and hepatocellular carcinoma (4,7,17,30,38,49).The HCV RNA-dependent RNA polymerase (NS5B) has a high frequency of incorrect nucleotide insertions, in the range of 10 Ϫ4 to 10 Ϫ5 base substitutions per site, which can result in the rapid generation of HCV quasispecies (37, 45). Because of this huge genetic diversity, HCV is currently classified into six major genotypes and more than 80 subtypes (44). Recombination may be another mechanism exploited by HCV to increase genetic diversity: naturally occurring intergenotypic recombinant viruses that often have their recombination points in the trans-membrane domains of NS2 were recently i...

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“…Limiting productive coinfection reduces the chances of recombination between HCV strains and the transfer of drug resistance or adaptive mutations between viral strains. Indeed, intra-and intergenotypic recombinant strains of HCV are rare even among patients with multiple infections (54)(55)(56), although a few examples have been detected (57)(58)(59)(60)(61). Interestingly, it has been suggested that coinfection with multiple strains of HCV leads to exacerbation of chronic HCV disease correlates (62).…”

Section: Discussionmentioning

confidence: 99%

Rapid Intracellular Competition between Hepatitis C Viral Genomes as a Result of Mitosis

Webster¹,

Wissing²,

Herker³

et al. 2013

J Virol

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). This process, termed superinfection exclusion, does not involve downregulation of surface viral receptors but instead occurs inside the cell at the level of RNA replication. The originally infecting virus may occupy replication niches or sequester host factors necessary for viral growth, preventing effective growth of viruses that enter the cell later. However, there appears to be an additional level of intracellular competition between viral genomes that occurs at or shortly following mitosis. In the setting of cellular division, when two viral replicons of equivalent fitness are present within a cell, each has an equal opportunity to exclude the other. In a population of dividing cells, the competition between viral genomes proceeds apace, randomly clearing one or the other genome from cells in the span of 9 to 12 days. These findings demonstrate a new mechanism of intracellular competition between HCV strains, which may act to further limit HCV's genetic diversity and ability to recombine in vivo. Hepatitis C virus (HCV) is a positive-stranded, enveloped single-stranded RNA (ssRNA) virus in the Flavivirus family. Currently, HCV infects more than 180 million people worldwide, and the associated morbidity and mortality are second only to those caused by HIV among emerging infections (1). HCV is primarily transmitted parenterally, but vertical and sexual transmission may also occur. After acute infection, approximately 25% of patients spontaneously clear the virus. The remaining patients are chronically infected and may go on to develop hepatic steatosis, cirrhosis, and hepatocellular carcinoma (2).Complete in vitro replication of an HCV molecular clone was first demonstrated in 2005, using the genotype 2a virus JFH-1 (3-5). This clone, isolated from a Japanese male patient with fulminant hepatitis (6), replicated robustly in Huh7 cells and produced infectious virions in the absence of cell culture adaptive mutations. The availability of this infectious molecular clone provided a powerful experimental model with many advantages over the previously described HCV replicons (7). More recently, other groups have constructed highly infectious intergenotypic chimeras of JFH-1 and other HCV strains by making substitutions in the region from core to a portion of NS2 (8-10). The genotype 2a/2a chimera Jc1 is especially infectious (10).HCV blocks infection by other incoming HCV virions through a process known as superinfection exclusion (11,12). This process appears to occur after the virus enters the cell, which is different from the superinfection exclusion mechanism found in many other viral systems in which downregulation of cell surface viral receptors is involved. The intracellular superinfection block during HCV infection might result from competition between the primary and secondary viruses involving sequestration of key host factor(s) needed for viral replication or through occupancy of replicative niches on the endoplasmic reticulum (ER) membrane.Superinfection exclusion has clear implications for treating H...

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Detection of hepatitis C virus natural recombinant RF1_2k/1b strain among intravenous drug users in Uzbekistan

Abstract: In conclusion, the finding of RF1_2k/1b in Central Asia indicates that the variant has wide geographic distribution. The PCR-based screening method developed in this study should be useful in further epidemiological and clinical studies on the recombination phenomenon in HCV.

Cited by 48 publications

References 27 publications

Hepatitis C virus genetic variability and evolution

Hepatitis C virus genetic variability and evolution

Naturally Occurring Hepatitis C Virus Subgenomic Deletion Mutants Replicate Efficiently in Huh-7 Cells and Are trans -Packaged In Vitro To Generate Infectious Defective Particles

Rapid Intracellular Competition between Hepatitis C Viral Genomes as a Result of Mitosis

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