Hepatitis C Virus Quasi‐Species Dynamics Predict Progression of Fibrosis after Liver Transplantation

Arenas, Juan; Gallegos‐Orozco, Juan F.; Laskus, Tomasz; Wilkinson, Jeff; Khatib, Amer; Fasola, Carlos G.; Adair, Debra; Radkowski, Marek; Kibler, Karen V.; Nowicki, Marek; Douglas, David D.; Williams, James L.; Netto, George J.; Mulligan, David C.; Klintmalm, Göran B.; Rakela, Jorge; Vargas, Hugo E.

doi:10.1086/386338

Cited by 36 publications

(38 citation statements)

References 40 publications

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“…HCV quasispecies diversity has been extensively studied in chronically infected humans, experimentally infected chimpanzees, human immunodeficiency virus (HIV)-coinfected subjects, and individuals on therapy and following blood product transfusions and liver transplantations (4,5,12,16,19,23,27,31,32,50,52,53,57,58,66,67). A strong CTL response targeting multiple epitopes has been correlated with plasma viremia resolution (11,34,36,42).…”

Section: Discussionmentioning

confidence: 99%

Wide Range of Quasispecies Diversity during Primary Hepatitis C Virus Infection

Herring

Tsui

Peddada

et al. 2005

J Virol

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Hepatitis C virus (HCV) infections may be initiated by multiple infectious particles, resulting in a genetically heterogeneous viral population, or by a single particle, leading to a clonal population in the initial stage of infection. To determine which of these scenarios is most common, we evaluated the genetic diversity of HCV quasispecies in 12 seronegative subjects with primary infection following community exposures, six acutely infected recipients of HCV-seropositive blood transfusions and six seropositive individuals with infections of undetermined durations. RNA isolated from plasma and a region of the HCV envelope gene including the first hypervariable region (HVR-1) was reverse transcription-PCR amplified and subcloned, and multiple plasmid clones were sequenced. Phylogenetic analysis indicated that all HCV variants clustered by individuals. Genetic distances among HCV variants within recently infected subjects ranged from 1 to 7.8%. On the basis of the estimated mutation rate of HCV in vivo and the Taq polymerase error rate, primary infection viral quasispecies were classified as genetically heterogeneous when the maximum sequence divergence between genetic variants in the same person was >3%. Heterogeneous quasispecies were detected in 4 of 12 preseroconversion subjects, 1 of 6 transfusion recipients, and 4 of 6 seropositive subjects. The high level of viral quasispecies genetic diversity found in at least a third of recently infected individuals is consistent with the transmission of multiple infectious particles. Community-acquired HCV infection, predominantly the result of needle sharing by injection drug users, therefore appears to be frequently initiated by the successful transmission of multiple viral variants.Hepatitis C virus (HCV) in plasma is typically found as a genetically heterogeneous, monophyletic population of viral variants often referred to as a quasispecies (14,18,49). The composition of such quasispecies changes rapidly in immunocompetent hosts, presumably because of the selection of escape variants that evade cellular and humoral immune responses (9,22,31,59,68) or because of superinfection with a divergent strain (25,55). Limited HCV evolution has been reported in immunocompromised chimpanzees and humans, possibly because of reduced immune selective pressures (6,44,47,66). The high mutation rate and short generation time of HCV therefore provide this virus with a high level of genetic adaptability, which may explain why as many as 80% of primary infections result in chronic infection with high-titer viremia (43).Because primary HCV infection is typically asymptomatic, subjects recently infected with HCV through contaminated needle sharing or other community exposures are difficult to identify. Consequently, the genetic diversity of the viral quasispecies during the very early preseroconversion phase of viremia remains largely unknown. The genetic diversity of preseroconversion plasma quasispecies is likely to be closely related to that of the inoculums since they are separated ...

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Section: Discussionmentioning

confidence: 99%

Wide Range of Quasispecies Diversity during Primary Hepatitis C Virus Infection

Herring

Tsui

Peddada

et al. 2005

J Virol

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“…The structural E1 and E2 genes evolve fastest (13) and have the strongest phylogenetic signal (40) as a result of encoding proteins that are recognized by the host immune system. Several studies report that some or most of the pretransplant diversity in the E1E2 region is lost during a viral bottleneck that follows transplantation, possibly reflecting the outgrowth of fitter variants (2,8,9,16,32,41,42). In contrast, some evidence suggests that posttransplant viral dynamics are more complex than a simple population bottleneck; for example, the dominant variant at 7 days posttransplant does not persist in later samples in all cases (2, 42), and the minor variant pretransplant can become dominant (14).…”

mentioning

confidence: 99%

“…Several studies report that some or most of the pretransplant diversity in the E1E2 region is lost during a viral bottleneck that follows transplantation, possibly reflecting the outgrowth of fitter variants (2,8,9,16,32,41,42). In contrast, some evidence suggests that posttransplant viral dynamics are more complex than a simple population bottleneck; for example, the dominant variant at 7 days posttransplant does not persist in later samples in all cases (2,42), and the minor variant pretransplant can become dominant (14). An observed bottleneck could be explained by a founder effect of colonization of the new liver, or result from methodological limitations such as consensus sequencing (28) or single-strand conformation polymorphisms (2,32) and the use of summary statistics (9,32,37,41), which fail to elucidate evolutionary relationships or structure (39,44); grouping results from multiple patients rendering data interpretation difficult (9,27,32,41,42); and temporally restric-tive sampling schemes that limit investigation of long-term evolutionary trends (8,9,16,37).…”

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confidence: 99%

Unexpected Maintenance of Hepatitis C Viral Diversity following Liver Transplantation

Gray

Strickland

Véras

et al. 2012

J Virol

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h Chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis in up to 20% of individuals, often requiring liver transplantation. Although the new liver is known to be rapidly reinfected, the dynamics and source of the reinfecting virus(es) are unclear, resulting in some confusion concerning the relationship between clinical outcome and viral characteristics. To clarify the dynamics of liver reinfection, longitudinal serum viral samples from 10 transplant patients were studied. Part of the E1/E2 region was sequenced, and advanced phylogenetic analysis methods were used in a multiparameter analysis to determine the history and ancestry of reinfecting lineages. Our results demonstrated the complexity of HCV evolutionary dynamics after liver transplantation, in which a large diverse population of viruses is transmitted and maintained for months to years. As many as 30 independent lineages in a single patient were found to reinfect the new liver. Several later posttransplant lineages were more closely related to older pretransplant viruses than to viruses detected immediately after transplantation. Although our data are consistent with a number of interpretations, the persistence of high viral genetic variation over long periods of time requires an active mechanism. We discuss possible scenarios, including frequency-dependent selection or variation in selective pressure among viral subpopulations, i.e., the population structure. The latter hypothesis, if correct, could have relevance to the success of newer direct-acting antiviral therapies.T he hepatitis C virus (HCV; family Flaviviridae, genus Hepacivirus) infects more than 180 million people worldwide and is a leading global cause of liver disease and cancer (3, 26). Since individuals can remain asymptomatic for decades, the true prevalence is potentially much greater than current estimates of ϳ3% of the world population (50). At present, no vaccine is available, and pharmacological treatment is only moderately successful, particularly for the most prevalent subtypes circulating in the United States and Europe (3), due in part to a prolonged asymptomatic phase of chronic infection that hinders early identification of HCV transmission among individuals. Although the use of direct-acting antiviral drugs (including two recently licensed protease inhibitors) offer improved sustained antiviral response rates (29), drug treatments will not be successful in all patients (47), and antiviral resistance is likely to play a significant role in treatment failure (21). Thus, chronic HCV infection remains a major public health concern.Liver cirrhosis develops in up to 20% of HCV-infected individuals, who will eventually require a liver transplant (3). However, the new liver is infected within minutes following transplant (16), serum viral load increases 10-to 20-fold relative to pretransplant levels (12), and the clinical course of disease is accelerated (11). Characteristics of the infecting virus and its anatomical source(s) are unknown, reflecting the lack of a pr...

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“…27 While in the above 2 settings lack of escape mutations is indicative of strong immune pressure leading to infection clearance, stability or reduction of quasispecies diversity and complexity in the natural course of chronic infection implies a weak immune response and may entail poor prognosis with respect to liver disease. 28,42,43 Similarly, narrowing of HVR1 complexity and diversity was associated with progressive liver disease in HCV/HIV coinfected hemophiliacs. 44 Despite the fact that HIV/HCV coinfection is common and may have grave clinical consequences, few studies have analyzed factors affecting HCV quasispecies in this setting.…”

Section: Discussionmentioning

confidence: 97%

“…19,[21][22][23] HCV quasispecies heterogeneity and dynamics has been extensively studied in various settings, including in those with acute and chronic hepatitis C, those receiving anti-HCV therapy, and following liver transplantation for HCV-related liver disease. [24][25][26][27][28] However, despite the high frequency of HCV/HIV coinfection, HCV quasispecies have rarely been analyzed in HIV-positive patients. In the few studies that were published, the number of analyzed patients was small and the role of associated factors could not be properly analyzed.…”

Section: H Epatitis C Virus (Hcv) Coinfection Is Commonmentioning

confidence: 99%