Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies
Abstract Hepatitis C virus (HCV) is a positive single-stranded RNA virus of enormous global health importance, with direct-acting antiviral therapies replacing an immunostimulatory interferon-based regimen. The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbat...
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| Veröffentlicht in: | Virology (New York, N.Y.) N.Y.), 2016-07, Vol.494, p.236-247 |
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| creator | Ramanan, Vyas Trehan, Kartik Ong, Mei.-Lyn Luna, Joseph M Hoffmann, Hans.-Heinrich Espiritu, Christine Sheahan, Timothy P Chandrasekar, Hamsika Schwartz, Robert E Christine, Kathleen S Rice, Charles M van Oudenaarden, Alexander Bhatia, Sangeeta N |
| description | Abstract Hepatitis C virus (HCV) is a positive single-stranded RNA virus of enormous global health importance, with direct-acting antiviral therapies replacing an immunostimulatory interferon-based regimen. The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have not been studied at the single-cell level, leaving a gap in our understanding of antiviral kinetics and host–virus interactions. Here, we demonstrate quantitative imaging of HCV genomes in multiple infection models, and multiplexing of positive and negative strand vRNAs and host antiviral RNAs. We capture the varying kinetics with which antiviral drugs with different mechanisms of action clear HCV infection, finding the NS5A inhibitor daclatasvir to induce a rapid decline in negative-strand viral RNAs. We also find that the induction of host antiviral genes upon interferon treatment is positively correlated with viral load in single cells. This study adds smFISH to the toolbox available for analyzing the treatment of RNA virus infections. |
| doi_str_mv | 10.1016/j.virol.2016.04.020 |
| format | Article |
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The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have not been studied at the single-cell level, leaving a gap in our understanding of antiviral kinetics and host–virus interactions. Here, we demonstrate quantitative imaging of HCV genomes in multiple infection models, and multiplexing of positive and negative strand vRNAs and host antiviral RNAs. We capture the varying kinetics with which antiviral drugs with different mechanisms of action clear HCV infection, finding the NS5A inhibitor daclatasvir to induce a rapid decline in negative-strand viral RNAs. We also find that the induction of host antiviral genes upon interferon treatment is positively correlated with viral load in single cells. This study adds smFISH to the toolbox available for analyzing the treatment of RNA virus infections.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1016/j.virol.2016.04.020</identifier><identifier>PMID: 27128351</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Cell Line ; Genome, Viral ; HCV ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepatitis C - diagnostic imaging ; Hepatitis C - drug therapy ; Hepatitis C - virology ; Hepatitis C virus ; Host-Pathogen Interactions - genetics ; Host–virus interactions ; Humans ; In Situ Hybridization, Fluorescence ; Infectious Disease ; Microscopy, Fluorescence ; Molecular Imaging ; RNA, Viral ; Single-Cell Analysis - methods ; Single-molecule FISH ; Viral Nonstructural Proteins - genetics ; Viral Nonstructural Proteins - metabolism ; Viral replication ; Virus Replication - drug effects ; Virus Replication - genetics</subject><ispartof>Virology (New York, N.Y.), 2016-07, Vol.494, p.236-247</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. 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The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have not been studied at the single-cell level, leaving a gap in our understanding of antiviral kinetics and host–virus interactions. Here, we demonstrate quantitative imaging of HCV genomes in multiple infection models, and multiplexing of positive and negative strand vRNAs and host antiviral RNAs. We capture the varying kinetics with which antiviral drugs with different mechanisms of action clear HCV infection, finding the NS5A inhibitor daclatasvir to induce a rapid decline in negative-strand viral RNAs. We also find that the induction of host antiviral genes upon interferon treatment is positively correlated with viral load in single cells. 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| subjects | Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Cell Line Genome, Viral HCV Hepacivirus - drug effects Hepacivirus - genetics Hepatitis C - diagnostic imaging Hepatitis C - drug therapy Hepatitis C - virology Hepatitis C virus Host-Pathogen Interactions - genetics Host–virus interactions Humans In Situ Hybridization, Fluorescence Infectious Disease Microscopy, Fluorescence Molecular Imaging RNA, Viral Single-Cell Analysis - methods Single-molecule FISH Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - metabolism Viral replication Virus Replication - drug effects Virus Replication - genetics |
| title | Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies |
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