Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release
Carolin Zitzmann,Lars Kaderali,Alan S. Perelson
Abstract:
Hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis, leading to severe complications. Understanding the mechanisms of HCV replication and transmission is crucial for developing effective treatments. In this study, we developed intracellular HCV replication models to investigate the secretion of HCV RNA and virus assembly and release. By fitting our models to in vitro data, we determined that initially, most secreted HCV RNA originates from intracellular cytosolic RNA. However, over time, secreted HCV RNA is equally derived from both the cytoplasm and replication compartments. Our findings also indicate that the rate of virus assembly and release is limited by host cell resources. We further explored the effects of direct acting antivirals on our models and discovered that even with reduced intracellular HCV RNA and extracellular virus concentration, low-level HCV RNA secretion may persist as long as intracellular RNA is available. This observation may explain the presence of detectable plasma HCV RNA levels at the end of treatment, even in patients who achieve sustained virologic response.
Introduction: HCV is a significant global health concern, with chronic infection leading to severe liver diseases. Antiviral therapies targeting HCV replication have high cure rates. HCV belongs to the Flaviviridae family and possesses a single plus-strand RNA genome. Replication compartments (RCs) are formed within host cells, providing an optimal environment for efficient viral genome replication and protection against antiviral immune responses.
Methods: We developed intracellular HCV replication and HCV RNA secretion models. These models incorporate different HCV RNA species, including RNA used for translation, RNA in RCs for replication, minus-strand RNA in RCs, and secreted HCV RNA. The models consider the secretion of RNA-containing particles, including exosomes and viral particles. The plus-strand RNA used for translation can be transferred to the RCs, where it is used for replication. Newly synthesized plus-strand RNA is then transported back for translation, and degradation rates are considered for the various RNA species.
Discussion: Previous models have investigated HCV dynamics and the impact of antiviral treatment but have lacked detailed understanding of intracellular events during replication and viral spread. The secretion of HCV RNA in exosomes is still not fully understood, but it has been shown that exosome-derived HCV RNA can infect other cells and stimulate immune responses. In this study, we distinguish between exosomal and viral particle secretion, providing insights into these two routes of transmission.
Citation: Zitzmann C, Kaderali L, Perelson AS (2020) Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release. PLoS Comput Biol 16(11): e1008421. https://doi.org/10.1371/journal.pcbi.1008421.
Editor: Kathryn Miller-Jensen, Yale University, UNITED STATES
Received: June 23, 2020; Accepted: October 6, 2020; Published: November 5, 2020
Data Availability:
All relevant data are within the manuscript and its Supporting Information files.
Funding:
Portions of this work were done under the auspices of the U.S. Department of Energy under contract 89233218CNA000001 and was supported by NIH grants R01-OD011095 (ASP), R01-AI028433 (ASP) and R01-AI 078881 (ASP). Parts of this work were supported by the BMBF through the ERASysAPP project SysVirDrug 031A602A (LK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests:
The authors have declared that no competing interests exist.
