Quantitative differences between intra-host HCV populations from persons with recently established and persistent infections

Abstract

SummaryBackgroundDetection of incident hepatitis C virus (HCV) infections is crucial for identification of outbreaks and development of public health interventions. However, there is no single diagnostic assay for distinguishing recent and persistent HCV infections. HCV exists in each infected host as a heterogeneous population of genomic variants, whose evolutionary dynamics remain incompletely understood. Genetic analysis of such viral populations can be applied to the detection of incident HCV infections and used to understand intra-host viral evolution.MethodsWe studied intra-host HCV populations sampled using next-generation sequencing from 98 recently and 256 persistently infected individuals. Genetic structure of the populations was evaluated using 245,878 viral sequences from these individuals and a set of selected parameters measuring their diversity, topological structure, complexity, strength of selection, epistasis, evolutionary dynamics, and physico-chemical properties.FindingsDistributions of the viral population parameters differ significantly between recent and persistent infections. A general increase in viral genetic diversity from recent to persistent infections is frequently accompanied by decline in genomic complexity and increase in structuredness of the HCV population, likely reflecting a high level of intra-host adaptation at later stages of infection. Using these findings, we developed a Machine Learning classifier for the infection staging, which yielded a detection accuracy of 95.22%, thus providing a higher accuracy than other genomic-based models.InterpretationThe detection of a strong association between several HCV genetic factors and stages of infection suggests that intra-host HCV population develops in a complex but regular and predictable manner in the course of infection. The proposed models may serve as a foundation of cyber-molecular assays for staging infection, that could potentially complement and/or substitute standard laboratory assays.FundingAZ and PS were supported by NIH grant 1R01EB025022. PIB was supported by GSU MBD fellowship.