Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing

A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F...

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Published inPLoS pathogens Vol. 8; no. 8; p. e1002880
Main Authors Li, Hui, Stoddard, Mark B., Wang, Shuyi, Blair, Lily M., Giorgi, Elena E., Parrish, Erica H., Learn, Gerald H., Hraber, Peter, Goepfert, Paul A., Saag, Michael S., Denny, Thomas N., Haynes, Barton F., Hahn, Beatrice H., Ribeiro, Ruy M., Perelson, Alan S., Korber, Bette T., Bhattacharya, Tanmoy, Shaw, George M.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.08.2012
Public Library of Science (PLoS)
Subjects
Acute Disease
BASIC BIOLOGICAL SCIENCES
Chronic illnesses
Colleges & universities
Disease transmission
Distribution
Diversification
DNA sequencing
Drug therapy
Female
Genetic aspects
Genome, Viral - genetics
Genome, Viral - immunology
Genomes
Health aspects
Hepacivirus - physiology
Hepatitis
Hepatitis C - genetics
Hepatitis C - immunology
Hepatitis C - transmission
Hepatitis C virus
Host-Pathogen Interactions
Humans
Infections
Male
Medicine
Microbiology
Mutation
Nucleotide sequencing
Parasitology
Phylogeny
Physiological aspects
RNA polymerase
RNA, Viral - genetics
RNA, Viral - immunology
Sequence Analysis, RNA
Tropical diseases
Vaccines
Viral genetics
Virology
Virulence (Microbiology)
Viruses
United States
Online AccessGet full text
ISSN1553-7374
1553-7366
1553-7374
DOI10.1371/journal.ppat.1002880

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Abstract A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
AbstractList A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures. Hepatitis C virus infects as many as 170 million people worldwide. Globally, there are seven major genotypes of HCV that differ by approximately 30% in nucleotide sequence. Importantly, the natural history of HCV infection is variable, ranging from spontaneous resolution to persistent viremia and chronic disease. Factors responsible for this variability in clinical outcome are unknown but likely involve a combination of viral and host determinants. To this end, a precise molecular identification of transmitted HCV genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of plasma viral RNA to identify transmitted viral genomes and their progeny in 17 subjects with acute infection. Numbers of transmitted viruses leading to productive clinical infection ranged from 1 to 37 or more (median = 4). Surprisingly, we found evidence of high multiplicity acute-to-acute HCV transmission in 3 of 17 subjects, which suggests that clinical transmission of HCV, like that of HIV-1, may be enhanced in early infection when virus titers are highest and neutralizing antibodies are absent. These results provide novel insight into HCV transmission and early virus diversification key to our understanding of virus natural history and response to drug selection and immune pressure.
  A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
Audience Academic
Author Korber, Bette T.
Giorgi, Elena E.
Wang, Shuyi
Hraber, Peter
Saag, Michael S.
Li, Hui
Hahn, Beatrice H.
Parrish, Erica H.
Ribeiro, Ruy M.
Perelson, Alan S.
Shaw, George M.
Learn, Gerald H.
Bhattacharya, Tanmoy
Stoddard, Mark B.
Denny, Thomas N.
Blair, Lily M.
Haynes, Barton F.
Goepfert, Paul A.
AuthorAffiliation 3 Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
5 University of Alabama at Birmingham, Birmingham, Alabama, United States of America
4 Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
2 Santa Fe Institute, Santa Fe, New Mexico, United States of America
1 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
University of Texas at Austin, United States of America
6 Duke University School of Medicine, Durham, North Carolina, United States of America
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/22927816$$D View this record in MEDLINE/PubMed
https://www.osti.gov/servlets/purl/1627904$$D View this record in Osti.gov
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ContentType Journal Article
Copyright COPYRIGHT 2012 Public Library of Science
2012 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Li H, Stoddard MB, Wang S, Blair LM, Giorgi EE, et al. (2012) Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing. PLoS Pathog 8(8): e1002880. doi:10.1371/journal.ppat.1002880
2012
2012 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Li H, Stoddard MB, Wang S, Blair LM, Giorgi EE, et al. (2012) Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing. PLoS Pathog 8(8): e1002880. doi:10.1371/journal.ppat.1002880
Copyright_xml – notice: COPYRIGHT 2012 Public Library of Science
– notice: 2012 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Li H, Stoddard MB, Wang S, Blair LM, Giorgi EE, et al. (2012) Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing. PLoS Pathog 8(8): e1002880. doi:10.1371/journal.ppat.1002880
– notice: 2012
– notice: 2012 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Li H, Stoddard MB, Wang S, Blair LM, Giorgi EE, et al. (2012) Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing. PLoS Pathog 8(8): e1002880. doi:10.1371/journal.ppat.1002880
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License This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
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AC52-06NA25396
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
The authors have declared that no competing interests exist.
Conceived and designed the experiments: HL LMB EEG PAG MSS TND BFH BHH RMR ASP BTK TB GMS. Performed the experiments: HL MBS SW EHP. Analyzed the data: HL LMB EEG GHL PH BHH RMR ASP BTK TB GMS. Contributed reagents/materials/analysis tools: LMB EEG PAG MSS TND BFH RMR ASP BTK TB. Wrote the paper: HL MBS SW LMB EEG EHP GHL PH PAG MSS TND BFH BHH RMR ASP BTK TB GMS.
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PublicationTitle PLoS pathogens
PublicationTitleAlternate PLoS Pathog
PublicationYear 2012
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Snippet A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and...
  A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis...
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SubjectTerms Acute Disease
BASIC BIOLOGICAL SCIENCES
Chronic illnesses
Colleges & universities
Disease transmission
Distribution
Diversification
DNA sequencing
Drug therapy
Female
Genetic aspects
Genome, Viral - genetics
Genome, Viral - immunology
Genomes
Health aspects
Hepacivirus - physiology
Hepatitis
Hepatitis C - genetics
Hepatitis C - immunology
Hepatitis C - transmission
Hepatitis C virus
Host-Pathogen Interactions
Humans
Infections
Male
Medicine
Microbiology
Mutation
Nucleotide sequencing
Parasitology
Phylogeny
Physiological aspects
RNA polymerase
RNA, Viral - genetics
RNA, Viral - immunology
Sequence Analysis, RNA
Tropical diseases
Vaccines
Viral genetics
Virology
Virulence (Microbiology)
Viruses
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Title Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing
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