Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release
Abstract
Hepatitis C virus (HCV) causes acute hepatitis C and can lead to life-threatening complications if it becomes chronic. The HCV genome is a single plus strand of RNA. Its intracellular replication is a spatiotemporally coordinated process of RNA translation upon cell infection, RNA synthesis within a replication compartment, and virus particle production. While HCV is mainly transmitted via mature infectious virus particles, it has also been suggested that HCV-infected cells can secrete HCV RNA carrying exosomes that can infect cells in a receptor independent manner. In order to gain insight into these two routes of transmission, we developed a series of intracellular HCV replication models that include HCV RNA secretion and/or virus assembly and release. Fitting our models to in vitro data, in which cells were infected with HCV, suggests that initially most secreted HCV RNA derives from intracellular cytosolic plus-strand RNA, but subsequently secreted HCV RNA derives equally from the cytoplasm and the replication compartments. Furthermore, our model fits to the data suggest that the rate of virus assembly and release is limited by host cell resources. Including the effects of direct acting antivirals in our models, we found that in spite of decreasing intracellular HCV RNA and extracellularmore »
- Authors:
-
[2];
[3]
- Univ. Medicine Greifswald (Germany); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Univ. Medicine Greifswald (Germany)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Publication Date:
- Research Org.:
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1807865
- Report Number(s):
- LA-UR-20-24443
Journal ID: ISSN 1553-7358
- Grant/Contract Number:
- 89233218CNA000001; R01-OD011095; R01-AI028433; R01-AI078881
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Computational Biology (Online)
- Additional Journal Information:
- Journal Name: PLoS Computational Biology (Online); Journal Volume: 16; Journal Issue: 11; Journal ID: ISSN 1553-7358
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Zitzmann, Carolin, Kaderali, Lars, and Perelson, Alan S. Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release. United States: N. p., 2020.
Web. doi:10.1371/journal.pcbi.1008421.
Zitzmann, Carolin, Kaderali, Lars, & Perelson, Alan S. Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release. United States. https://doi.org/10.1371/journal.pcbi.1008421
Zitzmann, Carolin, Kaderali, Lars, and Perelson, Alan S. Thu .
"Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release". United States. https://doi.org/10.1371/journal.pcbi.1008421. https://www.osti.gov/servlets/purl/1807865.
@article{osti_1807865,
title = {Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release},
author = {Zitzmann, Carolin and Kaderali, Lars and Perelson, Alan S.},
abstractNote = {Hepatitis C virus (HCV) causes acute hepatitis C and can lead to life-threatening complications if it becomes chronic. The HCV genome is a single plus strand of RNA. Its intracellular replication is a spatiotemporally coordinated process of RNA translation upon cell infection, RNA synthesis within a replication compartment, and virus particle production. While HCV is mainly transmitted via mature infectious virus particles, it has also been suggested that HCV-infected cells can secrete HCV RNA carrying exosomes that can infect cells in a receptor independent manner. In order to gain insight into these two routes of transmission, we developed a series of intracellular HCV replication models that include HCV RNA secretion and/or virus assembly and release. Fitting our models to in vitro data, in which cells were infected with HCV, suggests that initially most secreted HCV RNA derives from intracellular cytosolic plus-strand RNA, but subsequently secreted HCV RNA derives equally from the cytoplasm and the replication compartments. Furthermore, our model fits to the data suggest that the rate of virus assembly and release is limited by host cell resources. Including the effects of direct acting antivirals in our models, we found that in spite of decreasing intracellular HCV RNA and extracellular virus concentration, low level HCV RNA secretion may continue as long as intracellular RNA is available. This may possibly explain the presence of detectable levels of plasma HCV RNA at the end of treatment even in patients that ultimately attain a sustained virologic response.},
doi = {10.1371/journal.pcbi.1008421},
journal = {PLoS Computational Biology (Online)},
number = 11,
volume = 16,
place = {United States},
year = {Thu Nov 05 00:00:00 EST 2020},
month = {Thu Nov 05 00:00:00 EST 2020}
}
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