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:

Ke, Ruian ^[1]; Li, Hui ^[2]; Wang, Shuyi ^[2]; Ding, Wenge ^[2]; Ribeiro, Ruy M.  ^[3];

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• Search DOE PAGES for ORCID "0000-0002-3988-8241"
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Giorgi, Elena E. ^[4]; Bhattacharya, Tanmoy  ^[5];

• Search DOE PAGES for author "Bhattacharya, Tanmoy"
• Search DOE PAGES for ORCID "0000-0002-1060-652X"
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Barnard, Richard J. O. ^[6]; Hahn, Beatrice H. ^[2]; Shaw, George M. ^[2]; Perelson, Alan S. ^[7]

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+ Show Author Affiliations

1. Department of Mathematics, North Carolina State University, Raleigh, NC 27695,, Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545,
2. Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104,, Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104,
3. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545,, Laboratory of Biomathematics, Faculty of Medicine, University of Lisbon, 1600-276 Lisbon, Portugal,
4. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545,
5. Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545,, Santa Fe Institute, Santa Fe, NM 87501,
6. Department of Infectious Disease, Merck &, Co., Inc., Kenilworth, NJ 07033
7. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545,, Santa Fe Institute, Santa Fe, NM 87501,

Publication Date:

2018-07-09

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