Unexpected maintenance of hepatitis C viral diversity following liver transplantation - PubMed (original) (raw)

Unexpected maintenance of hepatitis C viral diversity following liver transplantation

Rebecca R Gray et al. J Virol. 2012 Aug.

Abstract

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.

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Figures

Fig 1

Fig 1

Sample genetic diversity in serum. Plots are shown for patients A to L. Sample genetic viral diversity was assessed for all samples in 10 HCV patients using maximum-likelihood corrected pairwise nucleotide distances for all sequences at a given time point. For each patient, the y axis shows estimated genetic diversity. The x axis represents time going forward. Each of the light gray vertical bars = 1 year. The gray shaded area represents the time after the transplant. Mean and standard error are denoted with a circle and bars.

Fig 2

Fig 2

Population genetic diversity. Plots are shown for patients A to L. For each patient, the y axis shows estimated genetic diversity. The x axis represents time going forward. Each of the vertical bars = 1 year. The gray shaded area represents the time after the transplant. The black curve gives the mean estimate of the BSP, and the red area indicates the 95% high posterior density intervals.

Fig 3

Fig 3

Bayesian phylogenies. Trees are shown for patients A to L where branches are scaled in time with vertical lines indicating years (drawn relative to the last sample). Terminal branches are colored according to the time of sampling: black = pretransplant, red = 1 to 3 months posttransplant, blue = 3 to 20 months posttransplant, green = >20 months posttransplant. Internal branches are colored according to the maximum-parsimony reconstruction of the time of sampling with a time-forward enforcement. Asterisks indicate posterior support > 0.9, and thick branches indicate a lineage containing a positively selected site.

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