Transmissibility of intra-host hepatitis C virus variants

David S Campo,Sumathi Ramachandran,June Zhang,Yury Khudyakov

doi:10.1186/s12864-017-4267-4

David S Campo, Sumathi Ramachandran + Show 2 more

Open Access

https://doi.org/10.1186/s12864-017-4267-4

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Journal: BMC Genomics	Publication Date: Dec 1, 2017
Citations: 9	License type: open-access

Affiliation: Centers for Disease Control and Prevention

Abstract

BackgroundIntra-host hepatitis C virus (HCV) populations are genetically heterogeneous and organized in subpopulations. With the exception of blood transfusions, transmission of HCV occurs via a small number of genetic variants, the effect of which is frequently described as a bottleneck. Stochasticity of transmission associated with the bottleneck is usually used to explain genetic differences among HCV populations identified in the source and recipient cases, which may be further exacerbated by intra-host HCV evolution and differential biological capacity of HCV variants to successfully establish a population in a new host.ResultsTransmissibility was formulated as a property that can be measured from experimental Ultra-Deep Sequencing (UDS) data. The UDS data were obtained from one large hepatitis C outbreak involving an epidemiologically defined source and 18 recipient cases. k-Step networks of HCV variants were constructed and used to identify a potential association between transmissibility and network centrality of individual HCV variants from the source. An additional dataset obtained from nine other HCV outbreaks with known directionality of transmission was used for validation.Transmissibility was not found to be dependent on high frequency of variants in the source, supporting the earlier observations of transmission of minority variants. Among all tested measures of centrality, the highest correlation of transmissibility was found with Hamming centrality (r = 0.720; p = 1.57 E-71). Correlation between genetic distances and differences in transmissibility among HCV variants from the source was found to be 0.3276 (Mantel Test, p = 9.99 E-5), indicating association between genetic proximity and transmissibility. A strong correlation ranging from 0.565–0.947 was observed between Hamming centrality and transmissibility in 7 of the 9 additional transmission clusters (p < 0.05).ConclusionsTransmission is not an exclusively stochastic process. Transmissibility, as formally measured in this study, is associated with certain biological properties that also define location of variants in the genetic space occupied by the HCV strain from the source. The measure may also be applicable to other highly heterogeneous viruses. Besides improving accuracy of outbreak investigations, this finding helps with the understanding of molecular mechanisms contributing to establishment of chronic HCV infection.

Highlights

Intra-host hepatitis C virus (HCV) populations are genetically heterogeneous and organized in subpopulations
Frequency of shared HCV variants The data available from the AW outbreak were especially amenable to analysis of transmissibility of intrahost HCV variants: (1) an epidemiologically established transmission from a single source case to 18 recipients over a 5-week period [22]; and (2) a large number of intra-host HCV hypervariable region 1 (HVR1) variants sampled from each case using Ultra-Deep Sequencing (UDS) [23]
The number of variants sampled from the source was not highest among all cases, the intra-host HCV population had the highest level of nucleotide diversity [24]

Summary

Introduction

Intra-host hepatitis C virus (HCV) populations are genetically heterogeneous and organized in subpopulations. Hepatitis C virus (HCV) infects nearly 3% of the world’s population and is a major cause of liver disease worldwide [1]. HCV infection is an important US public health problem, being the most common chronic bloodborne infection and the leading cause for liver transplantation [2]. Since 2007, HCV has surpassed Human Immunodeficiency Virus (HIV) as a cause of death in the United States [3]. It is estimated that 2.7–3.9 million people in the United States have chronic HCV infection and that > 15,000 die each year from HCV-related disease, with mortality expected to rise in the coming years [4]. Outbreaks of HCV infections are associated with unsafe injection practices, drug diversion, and other exposures to blood and blood products [5]

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