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Title: Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence

Abstract

RNA viruses exist as a genetically diverse quasispecies with extraordinary ability to adapt to abrupt changes in the host environment. However, the molecular mechanisms that contribute to their rapid adaptation and persistence in vivo are not well studied. Here, we probe hepatitis C virus (HCV) persistence by analyzing clinical samples taken from subjects who were treated with a second-generation HCV protease inhibitor. Frequent longitudinal viral load determinations and large-scale single-genome sequence analyses revealed rapid antiviral resistance development, and surprisingly, dynamic turnover of dominant drug-resistant mutant populations long after treatment cessation. We fitted mathematical models to both the viral load and the viral sequencing data, and the results provided strong support for the critical roles that superinfection and cure of infected cells play in facilitating the rapid turnover and persistence of viral populations. More broadly, our results highlight the importance of considering viral dynamics and competition at the intracellular level in understanding rapid viral adaptation. Thus, we propose a theoretical framework integrating viral and molecular mechanisms to explain rapid viral evolution, resistance, and persistence despite antiviral treatment and host immune responses.

Authors:
; ; ; ; ORCiD logo; ; ORCiD logo; ; ; ;
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Santa Fe Inst. (SFI), Santa Fe, NM (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1459484
Alternate Identifier(s):
OSTI ID: 1625021
Grant/Contract Number:  
AC52-06NA25396; R01-OD011095; R01-AI028433; R01-AI078881; R01-AI116868; U19-AI088791; P30-AI45008
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 30; Journal ID: ISSN 0027-8424
Publisher:
Proceedings of the National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; virus evolution; virus persistence; hepatitis C virus; phylodynamic modeling; mathematical modeling

Citation Formats

Ke, Ruian, Li, Hui, Wang, Shuyi, Ding, Wenge, Ribeiro, Ruy M., Giorgi, Elena E., Bhattacharya, Tanmoy, Barnard, Richard J. O., Hahn, Beatrice H., Shaw, George M., and Perelson, Alan S. Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence. United States: N. p., 2018. Web. doi:10.1073/pnas.1805267115.
Ke, Ruian, Li, Hui, Wang, Shuyi, Ding, Wenge, Ribeiro, Ruy M., Giorgi, Elena E., Bhattacharya, Tanmoy, Barnard, Richard J. O., Hahn, Beatrice H., Shaw, George M., & Perelson, Alan S. Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence. United States. doi:https://doi.org/10.1073/pnas.1805267115
Ke, Ruian, Li, Hui, Wang, Shuyi, Ding, Wenge, Ribeiro, Ruy M., Giorgi, Elena E., Bhattacharya, Tanmoy, Barnard, Richard J. O., Hahn, Beatrice H., Shaw, George M., and Perelson, Alan S. Mon . "Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence". United States. doi:https://doi.org/10.1073/pnas.1805267115.
@article{osti_1459484,
title = {Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence},
author = {Ke, Ruian and Li, Hui and Wang, Shuyi and Ding, Wenge and Ribeiro, Ruy M. and Giorgi, Elena E. and Bhattacharya, Tanmoy and Barnard, Richard J. O. and Hahn, Beatrice H. and Shaw, George M. and Perelson, Alan S.},
abstractNote = {RNA viruses exist as a genetically diverse quasispecies with extraordinary ability to adapt to abrupt changes in the host environment. However, the molecular mechanisms that contribute to their rapid adaptation and persistence in vivo are not well studied. Here, we probe hepatitis C virus (HCV) persistence by analyzing clinical samples taken from subjects who were treated with a second-generation HCV protease inhibitor. Frequent longitudinal viral load determinations and large-scale single-genome sequence analyses revealed rapid antiviral resistance development, and surprisingly, dynamic turnover of dominant drug-resistant mutant populations long after treatment cessation. We fitted mathematical models to both the viral load and the viral sequencing data, and the results provided strong support for the critical roles that superinfection and cure of infected cells play in facilitating the rapid turnover and persistence of viral populations. More broadly, our results highlight the importance of considering viral dynamics and competition at the intracellular level in understanding rapid viral adaptation. Thus, we propose a theoretical framework integrating viral and molecular mechanisms to explain rapid viral evolution, resistance, and persistence despite antiviral treatment and host immune responses.},
doi = {10.1073/pnas.1805267115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 30,
volume = 115,
place = {United States},
year = {2018},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: https://doi.org/10.1073/pnas.1805267115

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Cited by: 1 work
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