NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains

Benzine, Tiffany; Brandt, Ryan; Lovell, William C.; Yamane, Daisuke; Neddermann, Petra; De Francesco, Raffaele; Lemon, Stanley M.; Perelson, Alan S.; Ke, Ruian; McGivern, David R.; Randall, Glenn

doi:10.1371/journal.ppat.1006343

Title: NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains

Journal Article · Thu Jun 08 00:00:00 EDT 2017 · PLoS Pathogens

DOI: https://doi.org/10.1371/journal.ppat.1006343 · OSTI ID:1375872

Benzine, Tiffany ^[1]; Brandt, Ryan ^[2];

^[3]; Yamane, Daisuke ^[3];

^[4]; De Francesco, Raffaele ^[4]; Lemon, Stanley M. ^[1];

^[5]; Ke, Ruian ^[2];

^[1]; Randall, Glenn ^[6]

Univ. of North Carolina, Chapel Hill, NC (United States). Lineberger Comprehensive Cancer Center and Dept. of Medicine
North Carolina State Univ., Raleigh, NC (United States). Dept. of Mathematics
Univ. of North Carolina, Chapel Hill, NC (United States). Lineberger Comprehensive Cancer Center
National Inst. of Molecular Genetics (INGM), Milan (Italy)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
Univ. of Chicago, IL (United States)

We synthesized the Hepatitis C virus (HCV) RNA by the replicase complex (RC), a macromolecular assembly composed of viral non-structural proteins and cellular co-factors. Inhibitors of the HCV NS5A protein block formation of new RCs but do not affect RNA synthesis by preformed RCs. Without new RC formation, existing RCs turn over and are eventually lost from the cell. We aimed to use NS5A inhibitors to estimate the half-life of the functional RC of HCV. We compared different cell culture-infectious strains of HCV that may be grouped based on their sensitivity to lipid peroxidation: robustly replicating, lipid peroxidation resistant (LPO^R) viruses (e.g. JFH-1 or H77D) and more slowly replicating, lipid peroxidation sensitive (LPO^S) viruses (e.g. H77S.3 and N.2). Furthermore, in luciferase assays, LPO^S HCV strains declined under NS5A inhibitor therapy with much slower kinetics compared to LPO^R HCV strains. This difference in rate of decline was not observed for inhibitors of the NS5B RNAdependent RNA polymerase suggesting that the difference was not simply a consequence of differences in RNA stability. In further analyses, we compared two isoclonal HCV variants: the LPO^S H77S.3 and the LPO^R H77D that differ only by 12 amino acids. Differences in rate of decline between H77S.3 and H77D following NS5A inhibitor addition were not due to amino acid sequences in NS5A but rather due to a combination of amino acid differences in the non-structural proteins that make up the HCV RC. The mathematical modeling of intracellular HCV RNA dynamics suggested that differences in RC stability (half-lives of 3.5 and 9.9 hours, for H77D and H77S.3, respectively) are responsible for the different kinetics of antiviral suppression between LPO^S and LPO^R viruses. In nascent RNA capture assays, the rate of RNA synthesis decline following NS5A inhibitor addition was significantly faster for H77D compared to H77S.3 indicating different half-lives of functional RCs.

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Research Organization:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1375872

Report Number(s):: LA-UR--17-20265

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 6 Vol. 13; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Competing and noncompeting activities of miR-122 and the 5' exonuclease Xrn1 in regulation of hepatitis C virus replication Li, Y.; Masaki, T.; Yamane, D. Proceedings of the National Academy of Sciences, Vol. 110, Issue 5 https://doi.org/10.1073/pnas.1213515110	journal	December 2012
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Visualization of Double-Stranded RNA in Cells Supporting Hepatitis C Virus RNA Replication Targett-Adams, Paul; Boulant, Steeve; McLauchlan, John Journal of Virology, Vol. 82, Issue 5 https://doi.org/10.1128/jvi.01565-07	journal	December 2007
Compensatory Mutations in E1, p7, NS2, and NS3 Enhance Yields of Cell Culture-Infectious Intergenotypic Chimeric Hepatitis C Virus Yi, MinKyung; Ma, Yinghong; Yates, Jeremy Journal of Virology, Vol. 81, Issue 2 https://doi.org/10.1128/jvi.01890-06	journal	November 2006
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A sensor at the lipid‐protein interface: Lipid peroxidation controls hepatitis C virus replication Paul, David; Bartenschlager, Ralf Hepatology, Vol. 61, Issue 3 https://doi.org/10.1002/hep.27637	journal	January 2015
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Recruitment and Activation of a Lipid Kinase by Hepatitis C Virus NS5A Is Essential for Integrity of the Membranous Replication Compartment Reiss, Simon; Rebhan, Ilka; Backes, Perdita Cell Host & Microbe, Vol. 9, Issue 1 https://doi.org/10.1016/j.chom.2010.12.002	journal	January 2011
Continuous de novo generation of spatially segregated hepatitis C virus replication organelles revealed by pulse-chase imaging Wang, Hongliang; Tai, Andrew W. Journal of Hepatology, Vol. 66, Issue 1 https://doi.org/10.1016/j.jhep.2016.08.018	journal	January 2017
Understanding hepatitis C viral dynamics with direct-acting antiviral agents due to the interplay between intracellular replication and cellular infection dynamics Guedj, J.; Neumann, A. U. Journal of Theoretical Biology, Vol. 267, Issue 3 https://doi.org/10.1016/j.jtbi.2010.08.036	journal	December 2010
Discovery of Selective Small Molecule Type III Phosphatidylinositol 4-Kinase Alpha (PI4KIIIα) Inhibitors as Anti Hepatitis C (HCV) Agents Leivers, Anna L.; Tallant, Matthew; Shotwell, J. Brad Journal of Medicinal Chemistry, Vol. 57, Issue 5 https://doi.org/10.1021/jm400781h	journal	August 2013
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Competing and noncompeting activities of miR-122 and the 5' exonuclease Xrn1 in regulation of hepatitis C virus replication Li, Y.; Masaki, T.; Yamane, D. Proceedings of the National Academy of Sciences, Vol. 110, Issue 5 https://doi.org/10.1073/pnas.1213515110	journal	December 2012
Complete Replication of Hepatitis C Virus in Cell Culture Lindenbach, B. D. Science, Vol. 309, Issue 5734 https://doi.org/10.1126/science.1114016	journal	July 2005
Protein Friction Limits Diffusive and Directed Movements of Kinesin Motors on Microtubules Bormuth, V.; Varga, V.; Howard, J. Science, Vol. 325, Issue 5942 https://doi.org/10.1126/science.1174923	journal	August 2009
Fast Hepatitis C Virus RNA Elimination and NS5A Redistribution by NS5A Inhibitors Studied by a Multiplex Assay Approach Liu, Dandan; Ji, Juan; Ndongwe, Tanya P. Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 6 https://doi.org/10.1128/AAC.00223-15	journal	April 2015
The Cyclophilin Inhibitor SCY-635 Disrupts Hepatitis C Virus NS5A-Cyclophilin A Complexes Hopkins, Sam; Bobardt, Michael; Chatterji, Udayan Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 7 https://doi.org/10.1128/AAC.00693-12	journal	May 2012
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Small Molecules Targeting Hepatitis C Virus-Encoded NS5A Cause Subcellular Redistribution of Their Target: Insights into Compound Modes of Action Targett-Adams, P.; Graham, E. J. S.; Middleton, J. Journal of Virology, Vol. 85, Issue 13 https://doi.org/10.1128/JVI.00215-11	journal	April 2011
Hepatitis C Virus Infection Causes Cell Cycle Arrest at the Level of Initiation of Mitosis Kannan, R. P.; Hensley, L. L.; Evers, L. E. Journal of Virology, Vol. 85, Issue 16 https://doi.org/10.1128/JVI.00280-11	journal	June 2011
Regulation of Hepatitis C Virus Translation and Infectious Virus Production by the MicroRNA miR-122 Jangra, R. K.; Yi, M.; Lemon, S. M. Journal of Virology, Vol. 84, Issue 13 https://doi.org/10.1128/JVI.00417-10	journal	April 2010
Visualization of Double-Stranded RNA in Cells Supporting Hepatitis C Virus RNA Replication Targett-Adams, Paul; Boulant, Steeve; McLauchlan, John Journal of Virology, Vol. 82, Issue 5 https://doi.org/10.1128/JVI.01565-07	journal	December 2007
Compensatory Mutations in E1, p7, NS2, and NS3 Enhance Yields of Cell Culture-Infectious Intergenotypic Chimeric Hepatitis C Virus Yi, MinKyung; Ma, Yinghong; Yates, Jeremy Journal of Virology, Vol. 81, Issue 2 https://doi.org/10.1128/JVI.01890-06	journal	November 2006
Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase during the Hepatitis C Virus Life Cycle McGivern, David R.; Masaki, Takahiro; Lovell, William Journal of Virology, Vol. 89, Issue 10 https://doi.org/10.1128/JVI.03188-14	journal	March 2015
Quantitative Analysis of the Hepatitis C Virus Replication Complex Quinkert, D.; Bartenschlager, R.; Lohmann, V. Journal of Virology, Vol. 79, Issue 21 https://doi.org/10.1128/JVI.79.21.13594-13605.2005	journal	October 2005
Metabolism of Phosphatidylinositol 4-Kinase IIIα-Dependent PI4P Is Subverted by HCV and Is Targeted by a 4-Anilino Quinazoline with Antiviral Activity Bianco, Annalisa; Reghellin, Veronica; Donnici, Lorena PLoS Pathogens, Vol. 8, Issue 3 https://doi.org/10.1371/journal.ppat.1002576	journal	March 2012
Replication Vesicles are Load- and Choke-Points in the Hepatitis C Virus Lifecycle Binder, Marco; Sulaimanov, Nurgazy; Clausznitzer, Diana PLoS Pathogens, Vol. 9, Issue 8 https://doi.org/10.1371/journal.ppat.1003561	journal	August 2013
Hepatitis C Virus-Induced Cytoplasmic Organelles Use the Nuclear Transport Machinery to Establish an Environment Conducive to Virus Replication Neufeldt, Christopher J.; Joyce, Michael A.; Levin, Aviad PLoS Pathogens, Vol. 9, Issue 10 https://doi.org/10.1371/journal.ppat.1003744	journal	October 2013
The Hepatitis C Virus-Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites Neufeldt, Christopher J.; Joyce, Michael A.; Van Buuren, Nicholas PLOS Pathogens, Vol. 12, Issue 2 https://doi.org/10.1371/journal.ppat.1005428	journal	February 2016
Development of a Destabilized Firefly Luciferase Enzyme for Measurement of Gene Expression Leclerc, Gilles M.; Boockfor, Fredric R.; Faught, William J. BioTechniques, Vol. 29, Issue 3 https://doi.org/10.2144/00293rr02	journal	September 2000
Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment Reiss, Simon; Rebhan, Ilka; Backes, Perdita Cell Host & Microbe, Vol. 9, Issue 1, 32-45 https://doi.org/10.3410/f.9401964.10036068	journal	January 2011
Analysis of the hepatitis C viral kinetics during administration of two nucleotide analogues: sofosbuvir (GS-7977) and GS-0938 Guedj, Jeremie; Pang, Phillip S.; Denning, Jill Antiviral Therapy, Vol. 19, Issue 2 https://doi.org/10.3851/IMP2733	journal	January 2014

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