Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

Zitzmann, Carolin; Dächert, Christopher; Schmid, Bianca; van der Schaar, Hilde; van Hemert, Martijn; Perelson, Alan S.; van Kuppeveld, Frank J. M.; Bartenschlager, Ralf; Binder, Marco; Kaderali, Lars; Kasson, ed., Peter M.

doi:10.1371/journal.pcbi.1010423

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

Journal Article · Tue Apr 04 00:00:00 EDT 2023 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1010423· OSTI ID:1970049

Zitzmann, Carolin; ; Schmid, Bianca; van der Schaar, Hilde; van Hemert, Martijn; ; van Kuppeveld, Frank J. M.; Bartenschlager, Ralf; Binder, Marco; ; Kasson, ed., Peter M.

Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called “replication factories”), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and showed that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency, which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, such as polyprotein cleavage and viral RNA synthesis, may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the in vitro viral replication early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral growth.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1970049

Alternate ID(s):: OSTI ID: 1968339
OSTI ID: 1975019

Journal Information:: PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 4 Vol. 19; ISSN 1553-7358

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

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