@article{1e18a3c4bf664d94a2406ba1d3711d40,
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.",
author = "Timothy Sheahan and Naoko Imanaka and Svetlana Marukian and Marcus Dorner and Peng Liu and Alexander Ploss and Rice, {Charles M.}",
note = "Funding Information: This work was supported by National Research Service Award F32 AI084448-01 (T.P.S.), National Institute for Diabetes, Digesting and Kidney Diseases 5R01DK085713-05 (C.M.R), National Institute of Allergy and Infectious Diseases R01AI091707 (C.M.R.), and Clinical Translational Science Award (CTSA, RUCCTS Grant #8 UL1 TR000043 from the National Center for Advancing Translational Sciences [NCATS, NIH]). Additional funding was provided by the Greenberg Medical Research Institute and the Starr Foundation. A.P. is a recipient of the Liver Scholar Award from the American Liver Foundation. We would like to thank Wenxiang Zhang at the Rockefeller Genomics Core Facility and Juana Gonzales in the Translational Technology Core Laboratory for technical support. We would also like to thank S.M. Pecoraro Di Vittorio, J. Palarca, J. Sable, M.E. Castillo, S. Shirley, T. Friling, and B. Flatley for outstanding administrative and/or technical support. Lastly, we would like to thank M. Saeed and W. Schneider for helpful comments on this manuscript. The funding sources were not involved in the study design, collection, analysis, or interpretation of data or in the writing of the report. Dr. Rice is a shareholder of Apath, LLC, which holds commercial rights to some of the HCV-related R&D tools used in this study. ",
year = "2014",
month = feb,
day = "12",
doi = "10.1016/j.chom.2014.01.007",
language = "English (US)",
volume = "15",
pages = "190--202",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "2",
}