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

Journal Article · Mon Jul 09 00:00:00 EDT 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1805267115· OSTI ID:1459484

Ke, Ruian ^[1]; Li, Hui ^[2]; Wang, Shuyi ^[2]; Ding, Wenge ^[2]; Ribeiro, Ruy M.  ^[3]; Giorgi, Elena E. ^[4]; Bhattacharya, Tanmoy  ^[5]; Barnard, Richard J. O. ^[6]; Hahn, Beatrice H. ^[2]; Shaw, George M. ^[2]; Perelson, Alan S. ^[7]

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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,

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.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Santa Fe Inst. (SFI), Santa Fe, NM (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)
• Sponsoring Organization: USDOE; National Inst. of Health (NIH) (United States)
• Grant/Contract Number: AC52-06NA25396; R01-OD011095; R01-AI028433; R01-AI078881; R01-AI116868; U19-AI088791; P30-AI45008
• OSTI ID: 1459484
• Alternate ID(s): OSTI ID: 1625021
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Vol. 115 Journal Issue: 30; ISSN 0027-8424
• Publisher: Proceedings of the National Academy of Sciences
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
59 BASIC BIOLOGICAL SCIENCES
virus evolution
virus persistence
hepatitis C virus
phylodynamic modeling
mathematical modeling