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Title: Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes

Abstract

Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from 4-50 infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replicationmore » and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Lastly, our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [3];  [3];  [4]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Heidelberg Univ. (Germany)
  2. Johns Hopkins Univ., Baltimore, MD (United States)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. Univ. of Glasgow, Scotland (United Kingdom)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1259480
Grant/Contract Number:  
AC52-06NA25396; GM103452; DA016078l; EY001765
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Volume: 10; Journal Issue: 11; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Graw, Frederik, Balagopal, Ashwin, Kandathil, Abraham J., Ray, Stuart C., Thomas, David L., Ribeiro, Ruy M., Perelson, Alan S., and Yates, Andrew J. Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes. United States: N. p., 2014. Web. doi:10.1371/journal.pcbi.1003934.
Graw, Frederik, Balagopal, Ashwin, Kandathil, Abraham J., Ray, Stuart C., Thomas, David L., Ribeiro, Ruy M., Perelson, Alan S., & Yates, Andrew J. Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes. United States. https://doi.org/10.1371/journal.pcbi.1003934
Graw, Frederik, Balagopal, Ashwin, Kandathil, Abraham J., Ray, Stuart C., Thomas, David L., Ribeiro, Ruy M., Perelson, Alan S., and Yates, Andrew J. 2014. "Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes". United States. https://doi.org/10.1371/journal.pcbi.1003934. https://www.osti.gov/servlets/purl/1259480.
@article{osti_1259480,
title = {Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes},
author = {Graw, Frederik and Balagopal, Ashwin and Kandathil, Abraham J. and Ray, Stuart C. and Thomas, David L. and Ribeiro, Ruy M. and Perelson, Alan S. and Yates, Andrew J.},
abstractNote = {Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from 4-50 infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Lastly, our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.},
doi = {10.1371/journal.pcbi.1003934},
url = {https://www.osti.gov/biblio/1259480}, journal = {PLoS Computational Biology (Online)},
issn = {1553-7358},
number = 11,
volume = 10,
place = {United States},
year = {Thu Nov 13 00:00:00 EST 2014},
month = {Thu Nov 13 00:00:00 EST 2014}
}

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journal, February 2010


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Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice
journal, July 2012


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The specific infectivity of hepatitis C virus changes through its life cycle
journal, November 2012


Dynamics of Hepatitis C Virus Replication in Human Liver
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Hepatocellular proliferation in patients with chronic hepatitis C and persistently normal or abnormal aminotransferase levels
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A Comprehensive Hepatitis C Viral Kinetic Model Explaining Cure
journal, May 2010


Replication of hepatitis C virus
journal, May 2007


Hepatoimmunology: A perspective
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Selection Pressure From Neutralizing Antibodies Drives Sequence Evolution During Acute Infection With Hepatitis C Virus
journal, June 2009


Visualizing Hepatitis C Virus Infections in Human Liver by Two-Photon Microscopy
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Use of Laser Capture Microdissection to Map Hepatitis C Virus–Positive Hepatocytes in Human Liver
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Plasmacytoid dendritic cells as guardians in hepatitis C virus–infected liver
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Modelling dynamics of the type I interferon response to in vitro viral infection
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Hepatocyte proliferation in chronic hepatitis C: correlation with degree of liver disease and serum alpha-fetoprotein
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Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission
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Analysis of Hepatitis C Virus Decline during Treatment with the Protease Inhibitor Danoprevir Using a Multiscale Model
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Mathematical modelling of HCV infection: what can it teach us in the era of direct-acting antiviral agents?
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Works referencing / citing this record:

Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics
journal, June 2018


Modeling the Chronification Tendency of Liver Infections as Evolutionary Advantage
journal, March 2019


Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence
journal, July 2018


How is the effectiveness of immune surveillance impacted by the spatial distribution of spreading infections?
journal, August 2015


Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics
journal, October 2016


Building a mechanistic mathematical model of hepatitis C virus entry
journal, March 2019


Causes and Consequences of Spatial Within-Host Viral Spread
journal, November 2018


Building a mechanistic mathematical model of hepatitis C virus entry.
text, January 2019


Building a mechanistic mathematical model of hepatitis C virus entry
journal, June 2018


Building a mechanistic mathematical model of hepatitis C virus entry
journal, June 2018


Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus
journal, August 2016