title: Interferon lambda alleles predict innate antiviral immune responses and hepatitis C virus permissiveness.
abstract: Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHHs) approaching single-cell resolution. An innate antiviral immune signature dominated the transcriptional response but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection.
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors: Timothy
authors: T
authors: Sheahan
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors: Naoko
authors: N
authors: Imanaka
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; HemoShear, Charlottesville, VA 22902, USA.
authors: Svetlana
authors: S
authors: Marukian
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors: Marcus
authors: M
authors: Dorner
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors: Peng
authors: P
authors: Liu
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors: Alexander
authors: A
authors: Ploss
authors: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA. Electronic address: ricec@mail.rockefeller.edu.
authors: Charles M
authors: CM
authors: Rice
mesh_terms: D000483:Alleles; D002478:Cells, Cultured; D004198:Disease Susceptibility; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007378:Interleukins / Q000235:genetics* / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D007378:Interleukins