Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles
Sandra Ciesek,Sandra Westhaus,Melanie Wicht,Ilka Wappler,Sylvana Henschen,Christoph Sarrazin,Nabila Hamdi,Ahmed Ihab Abdelaziz,Christian P. Strassburg,Heiner Wedemeyer,Michael P. Manns,Thomas Pietschmann,Thomas von Hahn +12 more
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TLDR
It is shown that murine OCLN can sustain HCVcc entry, albeit with about 5-fold reduced efficiency compared to that of human OCLn, and the frequency of coding nonsynonymous single nucleotide polymorphisms present in the human population is reported and determines their ability to function as HCV (co)receptors.Abstract:
Hepatitis C virus (HCV) is characterized by a narrow host range and high interindividual variability in the clinical course of infection. Both of these traits are thought to be largely due to genetic variation between species and between individual hosts. The tight junction component occludin (OCLN) is essential for HCV entry into host cells, and the differences between human and murine OCLN are thought to account in part for the inability of HCV to infect mice and hence preclude their use as a convenient small-animal model. This study assesses the impact of genetic variation in OCLN on cell culture-grown HCV (HCVcc) using a newly generated and characterized OCLNlow subclone of the Huh-7.5 cell line (Huh-7.5 subclone in which endogenous OCLN expression has been downregulated by a short hairpin RNA). We report the frequency of coding nonsynonymous single nucleotide polymorphisms, i.e., polymorphisms resulting in amino acid exchanges, present in the human population and determine their ability to function as HCV (co)receptors. Moreover, we show that murine OCLN can sustain HCVcc entry, albeit with about 5-fold reduced efficiency compared to that of human OCLN. This reduction in efficiency is due solely to two amino acid residues previously identified by others using an HCV pseudoparticle approach. Finally, we use the Huh-7.5/OCLNlow cell line to show that HCV spread between neighboring cells is strictly dependent on OCLN.read more
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The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry.
Sandra Ciesek,Thomas von Hahn,Che C. Colpitts,Luis M. Schang,Martina Friesland,Jörg Steinmann,Michael P. Manns,Michael Ott,Heiner Wedemeyer,Philip Meuleman,Thomas Pietschmann,Eike Steinmann +11 more
TL;DR: The green tea molecule, EGCG, potently inhibits HCV entry and could be part of an antiviral strategy aimed at the prevention of HCV reinfection after liver transplantation.
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The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry
Gerrit Gehring,Katrin Rohrmann,Nkacheh Atenchong,Eva Mittler,Stephan Becker,Franziska Dahlmann,Stefan Pöhlmann,Florian W. R. Vondran,Sascha David,Michael P. Manns,Sandra Ciesek,Thomas von Hahn +11 more
TL;DR: It is discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during anti-arrhythmic therapy.
Journal ArticleDOI
Evolution of genetic and genomic features unique to the human lineage.
TL;DR: An overview of the identification and study of genetic and genomic changes that are unique to their species have accelerated, and the authors are entering a golden age of human evolutionary genomics.
Journal ArticleDOI
Apolipoprotein E Codetermines Tissue Tropism of Hepatitis C Virus and Is Crucial for Viral Cell-to-Cell Transmission by Contributing to a Postenvelopment Step of Assembly
Kathrin Hueging,Mandy Doepke,Gabrielle Vieyres,Dorothea Bankwitz,Anne Frentzen,Juliane Doerrbecker,Frauke Gumz,Sibylle Haid,Benno Wölk,Lars Kaderali,Thomas Pietschmann +10 more
TL;DR: It is reported that production of HCV trans-complemented particles (HCVTCP) from nonliver cells depends on ectopic expression of apolipoprotein E (ApoE) and highlighted ApoE as a host factor codetermining HCV tissue tropism due to its involvement in a late assembly step and viral cell-to-cell transmission.
Journal ArticleDOI
CD81 and hepatitis C virus (HCV) infection.
TL;DR: The current knowledge on the involvement of CD81 in the HCV lifecycle, as well as in the immune response to HCV infection, is detailed.
References
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Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
Dongliang Ge,Jacques Fellay,Alexander J. Thompson,Jason Simon,Kevin V. Shianna,Thomas J. Urban,Erin L. Heinzen,Ping Qiu,Arthur H. Bertelsen,Andrew J. Muir,Mark S. Sulkowski,John G. McHutchison,David Goldstein +12 more
TL;DR: It is reported that a genetic polymorphism near the IL28B gene, encoding interferon-λ-3 (IFN-α-2a) is associated with an approximately twofold change in response to treatment, both among patients of European ancestry and African-Americans.
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Global epidemiology of hepatitis C virus infection
TL;DR: Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.
Journal ArticleDOI
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David Altshuler,Richard A. Gibbs,Leena Peltonen,Emmanouil T. Dermitzakis,Stephen F. Schaffner,Fuli Yu,Penelope E. Bonnen,de Bakker Piw.,Panagiotis Deloukas,Stacey Gabriel,R. Gwilliam,Sarah E. Hunt,Michael Inouye,Xiaoming Jia,Aarno Palotie,Melissa Parkin,Pamela Whittaker,Kyle Chang,Alicia Hawes,Lora Lewis,Yanru Ren,D Wheeler,Donna M. Muzny,Chris P. Barnes,Katayoon Darvishi,Matthew E. Hurles,Joshua M. Korn,K. Kristiansson,Charles Lee,S A McCarrol,James Nemesh,Alon Keinan,Stephen B. Montgomery,Samuela Pollack,Alkes L. Price,Nicole Soranzo,Claudia Gonzaga-Jauregui,Verneri Anttila,Wendy Brodeur,Mark J. Daly,Stephen Leslie,Gil McVean,Loukas Moutsianas,Huy Nguyen,Qingrun Zhang,Ghori Mjr.,Ralph McGinnis,William M. McLaren,Fumihiko Takeuchi,Sharon R. Grossman,Ilya Shlyakhter,Elizabeth Hostetter,Pardis C. Sabeti,Clement Adebamowo,Morris W. Foster,Deborah R. Gordon,Julio Licinio,M C Manca,Patricia A. Marshall,Ichiro Matsuda,D Ngare,Vivian Ota Wang,D Reddy,Charles N. Rotimi,Charmaine D.M. Royal,Richard R. Sharp,Changqing Zeng,Lisa D. Brooks,Jean E. McEwen +68 more
TL;DR: An expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.
Journal ArticleDOI
Binding of Hepatitis C Virus to CD81
Piero Pileri,Yasushi Uematsu,Susanna Campagnoli,Giuliano Galli,Fabiana Falugi,Roberto Petracca,Amy J. Weiner,Michael Houghton,Domenico Rosa,Guido Grandi,Sergio Abrignani +10 more
TL;DR: Recombinant molecules containing this loop bound HCV and antibodies that neutralize HCV infection in vivo inhibited virus binding to CD81 in vitro.
Journal ArticleDOI
Genetic variation in IL28B and spontaneous clearance of hepatitis C virus
David L. Thomas,Chloe L. Thio,Maureen P. Martin,Ying Qi,Dongliang Ge,Colm O'hUigin,Judith R. Kidd,Kenneth K. Kidd,Salim I. Khakoo,Graeme J.M. Alexander,James J. Goedert,Gregory D. Kirk,Sharyne M. Donfield,Hugo R. Rosen,Leslie H. Tobler,Michael P. Busch,John G. McHutchison,David Goldstein,Mary Carrington +18 more
TL;DR: It is shown that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry, the strongest and most significant genetic effect associated with natural clearance ofHCV.