Virion-Independent Transfer of Replication-Competent Hepatitis C Virus RNA between Permissive Cells

ABSTRACT In this study, we show that replication-competent subgenomic hepatitis C virus (HCV) RNA can be transferred to permissive Huh7 cells, leading to the establishment of viral RNA replication. Further, we show that these events are mediated by exosomes rather than infectious virus particles. If similar events occur in vivo, this could represent a novel, albeit inefficient, mechanism of viral spread and immune escape.

[1]  K. Kodys,et al.  Exosomes from Hepatitis C Infected Patients Transmit HCV Infection and Contain Replication Competent Viral RNA in Complex with Ago2-miR122-HSP90 , 2014, PLoS pathogens.

[2]  Jeroen A. A. Demmers,et al.  Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells , 2013, Proceedings of the National Academy of Sciences.

[3]  F. Chisari,et al.  Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. , 2012, Cell host & microbe.

[4]  Y. Igarashi,et al.  Sphingolipid-modulated Exosome Secretion Promotes Clearance of Amyloid-β by Microglia , 2012, The Journal of Biological Chemistry.

[5]  Clotilde Théry,et al.  Exosome Secretion: Molecular Mechanisms and Roles in Immune Responses , 2011, Traffic.

[6]  Haruhisa Iguchi,et al.  Competitive Interactions of Cancer Cells and Normal Cells via Secretory MicroRNAs* , 2011, The Journal of Biological Chemistry.

[7]  N. Raab-Traub,et al.  Microvesicles and Viral Infection , 2011, Journal of Virology.

[8]  Wen-Lang Lin,et al.  Intercellular nanovesicle‐mediated microRNA transfer: A mechanism of environmental modulation of hepatocellular cancer cell growth , 2011, Hepatology.

[9]  M. Caplan,et al.  Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling , 2010, The Journal of cell biology.

[10]  M. Caplan,et al.  Exosome‐release of beta‐catenin: A novel mechanism to antagonize Wnt signaling , 2010 .

[11]  Y. Matsuki,et al.  Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells*♦ , 2010, The Journal of Biological Chemistry.

[12]  F. Chisari,et al.  Plasmacytoid dendritic cells sense hepatitis C virus–infected cells, produce interferon, and inhibit infection , 2010, Proceedings of the National Academy of Sciences.

[13]  F. Zoulim,et al.  Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains , 2009, PLoS pathogens.

[14]  Petra Schwille,et al.  Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes , 2008, Science.

[15]  F. Chisari,et al.  Cellular Determinants of Hepatitis C Virus Assembly, Maturation, Degradation, and Secretion , 2007, Journal of Virology.

[16]  F. Chisari,et al.  Differential Biophysical Properties of Infectious Intracellular and Secreted Hepatitis C Virus Particles , 2006, Journal of Virology.

[17]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[18]  D. Burton,et al.  Robust hepatitis C virus infection in vitro. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Mizokami,et al.  Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. , 2003, Gastroenterology.

[20]  K. Agarwal,et al.  Hepatitis C virus particles of different density in the blood of chronically infected immunocompetent and immunodeficient patients: Implications for virus clearance by antibody , 2002, Journal of medical virology.

[21]  R. Bartenschlager,et al.  Persistent and Transient Replication of Full-Length Hepatitis C Virus Genomes in Cell Culture , 2002, Journal of Virology.

[22]  D. Bradley,et al.  Hepatitis C virus: Buoyant density if the factor VIII‐derived isolate in sucrose , 1991, Journal of medical virology.