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Title: Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification

Abstract

Despite the recent development of highly effective anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and development of an effective vaccine. A precise molecular identification of transmitted/founder (T/F) HCV genomes that lead to productive clinical infection could play a critical role in vaccine research, as it has for HIV-1. However, the replication schema of these two RNA viruses differ substantially, as do viral responses to innate and adaptive host defenses. These differences raise questions as to the certainty of T/F HCV genome inferences, particularly in cases where multiple closely related sequence lineages have been observed. To clarify these issues and distinguish between competing models of early HCV diversification, we examined seven cases of acute HCV infection in humans and chimpanzees, including three examples of virus transmission between linked donors and recipients. Using single-genome sequencing (SGS) of plasma vRNA, we found that inferred T/F sequences in recipients were identical to viral sequences in their respective donors. Early in infection, HCV genomes generally evolved according to a simple model of random evolution where the coalescent corresponded to the T/F sequence. Closely related sequencemore » lineages could be explained by high multiplicity infection from a donor whose viral sequences had undergone a pretransmission bottleneck due to treatment, immune selection, or recent infection. These findings validate SGS, together with mathematical modeling and phylogenetic analysis, as a novel strategy to infer T/F HCV genome sequences.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [1];  [1];  [4];  [5];  [6];  [2];  [7];  [8];  [1]
+ Show Author Affiliations
  1. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Medicine and Microbiology
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). T-Division
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). T-Division; Stanford Univ., CA (United States). Dept. of Biology
  4. National Inst. of Health (NIH), Bethesda, MD (United States). Dept. of Transfusion Medicine
  5. Univ. of California, San Francisco, CA (United States). Blood Systems Research Inst.
  6. Icahn School of Medicine at Mount Sinai, New York, NY (United States). Division of Infectious Diseases
  7. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group
  8. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). T-Division; Santa Fe Inst. (SFI), Santa Fe, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1626075
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 90; Journal Issue: 1; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Virology

Citation Formats

Li, Hui, Stoddard, Mark B., Wang, Shuyi, Giorgi, Elena E., Blair, Lily M., Learn, Gerald H., Hahn, Beatrice H., Alter, Harvey J., Busch, Michael P., Fierer, Daniel S., Ribeiro, Ruy M., Perelson, Alan S., Bhattacharya, Tanmoy, and Shaw, George M. Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification. United States: N. p., 2015. Web. doi:10.1128/jvi.02156-15.
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Li, Hui, Stoddard, Mark B., Wang, Shuyi, Giorgi, Elena E., Blair, Lily M., Learn, Gerald H., Hahn, Beatrice H., Alter, Harvey J., Busch, Michael P., Fierer, Daniel S., Ribeiro, Ruy M., Perelson, Alan S., Bhattacharya, Tanmoy, & Shaw, George M. Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification. United States. https://doi.org/10.1128/jvi.02156-15
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Li, Hui, Stoddard, Mark B., Wang, Shuyi, Giorgi, Elena E., Blair, Lily M., Learn, Gerald H., Hahn, Beatrice H., Alter, Harvey J., Busch, Michael P., Fierer, Daniel S., Ribeiro, Ruy M., Perelson, Alan S., Bhattacharya, Tanmoy, and Shaw, George M. Wed . "Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification". United States. https://doi.org/10.1128/jvi.02156-15. https://www.osti.gov/servlets/purl/1626075.
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@article{osti_1626075,
title = {Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification},
author = {Li, Hui and Stoddard, Mark B. and Wang, Shuyi and Giorgi, Elena E. and Blair, Lily M. and Learn, Gerald H. and Hahn, Beatrice H. and Alter, Harvey J. and Busch, Michael P. and Fierer, Daniel S. and Ribeiro, Ruy M. and Perelson, Alan S. and Bhattacharya, Tanmoy and Shaw, George M.},
abstractNote = {Despite the recent development of highly effective anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and development of an effective vaccine. A precise molecular identification of transmitted/founder (T/F) HCV genomes that lead to productive clinical infection could play a critical role in vaccine research, as it has for HIV-1. However, the replication schema of these two RNA viruses differ substantially, as do viral responses to innate and adaptive host defenses. These differences raise questions as to the certainty of T/F HCV genome inferences, particularly in cases where multiple closely related sequence lineages have been observed. To clarify these issues and distinguish between competing models of early HCV diversification, we examined seven cases of acute HCV infection in humans and chimpanzees, including three examples of virus transmission between linked donors and recipients. Using single-genome sequencing (SGS) of plasma vRNA, we found that inferred T/F sequences in recipients were identical to viral sequences in their respective donors. Early in infection, HCV genomes generally evolved according to a simple model of random evolution where the coalescent corresponded to the T/F sequence. Closely related sequence lineages could be explained by high multiplicity infection from a donor whose viral sequences had undergone a pretransmission bottleneck due to treatment, immune selection, or recent infection. These findings validate SGS, together with mathematical modeling and phylogenetic analysis, as a novel strategy to infer T/F HCV genome sequences.},
doi = {10.1128/jvi.02156-15},
journal = {Journal of Virology},
number = 1,
volume = 90,
place = {United States},
year = {Wed Oct 14 00:00:00 EDT 2015},
month = {Wed Oct 14 00:00:00 EDT 2015}
}
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https://doi.org/10.1128/jvi.02156-15
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Figures / Tables:

FIG 1 FIG 1: HCV sequence diversity in acutely infected human subject 110069. A maximum-likelihood (ML) mid-point rooted phylogenetic tree (A) and Highlighter plots (C and D) of nearly full length plasma vRNA sequences spanning the initial 6-month infection period are depicted. Plasma viral load kinetics (B) are also depicted, and themore » sequences are color coded to correspond to sampling time points determined from the first vRNA-positive/antibody-negative time point (blue, day 2; red, day 17; green, day 142). One month earlier, the HCV vRNA and antibody tests were negative. HCV antibody tests were negative through day 17 but were positive at the next sampled time point on day 146. The tree and the Highlighter plot reveal productive clinical infection by four T/F viruses (T/F lineages 1 to 4). Viral diversity is indicated by the scale bar and bootstrap values are shown. In the Highlighter (C), tick marks are color coded to indicate nucleotide substitutions by A (green), T (red), C (blue), or G (orange) compared to the consensus sequence of the first time point (TP1). In panel D, tick marks denote synonymous (green) or nonsynonymous (red) substitutions.« less
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    Works referencing / citing this record:

    Clearance of hepatitis C virus is associated with early and potent but narrowly-directed, Envelope-specific antibodies
    journal, September 2019

    High multiplicity of infection following transplantation of hepatitis C virus–positive organs
    journal, June 2019

    • Zahid, Muhammad N.; Wang, Shuyi; Learn, Gerald H.
    • Journal of Clinical Investigation, Vol. 129, Issue 8
    • DOI: 10.1172/jci127203
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