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1. Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS

Author

Pallett, Laura J., Swadling, Leo, Diniz, Mariana, Maini, Alexander A., Schwabenland, Marius, Gasull, Adrià Dalmau, Davies, Jessica, Kucykowicz, Stephanie, Skelton, Jessica K., Thomas, Niclas, Schmidt, Nathalie M., Amin, Oliver E., Gill, Upkar S., Stegmann, Kerstin A., Burton, Alice R., Stephenson, Emily, Reynolds, Gary, Whelan, Matt, Sanchez, Jenifer, de Maeyer, Roel, Thakker, Clare, Suveizdyte, Kornelija, Uddin, Imran, Ortega-Prieto, Ana M., Grant, Charlotte, Froghi, Farid, Fusai, Giuseppe, Lens, Sabela, Pérez-del-Pulgar, Sofia, Al-Akkad, Walid, Mazza, Giuseppe, Noursadeghi, Mahdad, Akbar, Arne, Kennedy, Patrick T. F., Davidson, Brian R., Prinz, Marco, Chain, Benjamin M., Haniffa, Muzlifah, Gilroy, Derek W., Dorner, Marcus, Bengsch, Bertram, Schurich, Anna, and Maini, Mala K.

Published
2023
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4. Author Correction: Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Author

Liu, Peter Jianrui, Harris, James M., Marchi, Emanuele, D’Arienzo, Valentina, Michler, Thomas, Wing, Peter A. C., Magri, Andrea, Ortega-Prieto, Ana Maria, van de Klundert, Maarten, Wettengel, Jochen, Durantel, David, Dorner, Marcus, Klenerman, Paul, Protzer, Ulrike, Giotis, Efstathios S., and McKeating, Jane A.

Published
2020
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5. Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Author

Liu, Peter Jianrui, Harris, James M., Marchi, Emanuele, D’Arienzo, Valentina, Michler, Thomas, Wing, Peter A. C., Magri, Andrea, Ortega-Prieto, Ana Maria, van de Klundert, Maarten, Wettengel, Jochen, Durantel, David, Dorner, Marcus, Klenerman, Paul, Protzer, Ulrike, Giotis, Efstathios S., and McKeating, Jane A.

Published
2020
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10. Animal Models for Hepatitis C

Author

Billerbeck, Eva, de Jong, Ype, Dorner, Marcus, de la Fuente, Cynthia, Ploss, Alexander, Aktories, Klaus, Series Editor, Compans, Richard W., Series Editor, Cooper, Max D., Series Editor, Galan, Jorge E., Series Editor, Gleba, Yuri Y., Series Editor, Honjo, Tasuku, Series Editor, Kawaoka, Yoshihiro, Series Editor, Koprowski, Hilary, Honorary Editor, Malissen, Bernard, Series Editor, Melchers, Fritz, Series Editor, Oldstone, Michael B. A., Series Editor, Rappuoli, Rino, Series Editor, Vogt, Peter K., Series Editor, and Bartenschlager, Ralf, editor

Published
2013
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15. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Author

Horwitz, Joshua A., Halper-Stromberg, Ariel, Mouquet, Hugo, Gitlin, Alexander D., Tretiakova, Anna, Eisenreich, Thomas R., Malbec, Marine, Gravemann, Sophia, Billerbeck, Eva, Dorner, Marcus, Büning, Hildegard, Schwartz, Olivier, Knops, Elena, Kaiser, Rolf, Seaman, Michael S., Wilson, James M., Rice, Charles M., Ploss, Alexander, Bjorkman, Pamela J., Klein, Florian, and Nussenzweig, Michel C.

Published
2013

18. CD8+ T cell acquisition of the LPS receptor within the hepatic stroma shapes anti-viral/anti-tumour potential

Author

Pallett, Laura J., primary, Diniz, Mariana, additional, Swadling, Leo, additional, Skelton, Jessica, additional, Maini, Alexander, additional, Davies, Jessica, additional, Kucykowicz, Stephanie, additional, Schmidt, Nathalie, additional, Amin, Oliver E., additional, Gill, Upkar, additional, Burton, Alice, additional, Sanchez, Jenifer, additional, Fusai, Giuseppe, additional, Lens, Sabela, additional, Pérez-del-Pulgar, Sofía, additional, Kennedy, Patrick, additional, Davidson, Brian R., additional, Haniffa, Muzlifah, additional, Gilroy, Derek, additional, Dorner, Marcus, additional, Schurich, Anna, additional, and Maini, Mala, additional

Published
2022
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21. Completion of the entire hepatitis C virus life cycle in genetically humanized mice

Author

Dorner, Marcus, Horwitz, Joshua A., Donovan, Bridget M., Labitt, Rachael N., Budell, William C., Friling, Tamar, Vogt, Alexander, Catanese, Maria Teresa, Satoh, Takashi, Kawai, Taro, Akira, Shizuo, Law, Mansun, Rice, Charles M., and Ploss, Alexander

Subjects
Nucleotide sequencing -- Methods, DNA sequencing -- Methods, Hepatitis C virus -- Genetic aspects, Mice -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

More than 130 million people worldwide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective against HCV infection, and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry (1), we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice (2). Here we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry, but innate and adaptive immune responses restrict HCV infection in vivo. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viraemia over several weeks. In mice lacking the essential cellular cofactor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes invivo. Persistently infected mice produce denovoinfectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing evidence for the completion of the entire HCV life cycle in inbred mice. This genetically humanized mouse model opens new opportunities to dissect genetically HCV infection invivoand provides an important preclinical platform for testing and prioritizing drug candidates and may also have utility for evaluating vaccine efficacy., The narrow species tropism of HCV is incompletely understood. Mouse cells do not support viral entry and inefficiently replicate HCV RNA, but do support virion assembly and release. HCV uses [...]

Published
2013

22. Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection

Author

Guermonprez, Pierre, Helft, Julie, Claser, Carla, Deroubaix, Stephanie, Karanje, Henry, Gazumyan, Anna, Darasse-Jeze, Guillaume, Telerman, Stephanie B., Breton, Gaelle, Schreiber, Heidi A., Frias-Staheli, Natalia, Billerbeck, Eva, Dorner, Marcus, Rice, Charles M., Ploss, Alexander, Klein, Florian, Swiecki, Melissa, Colonna, Marco, Kamphorst, Alice O., Meredith, Matthew, Niec, Rachel, Takacs, Constantin, Mikhail, Fadi, Hari, Aswin, Bosque, David, Eisenreich, Tom, Merad, Miriam, Shi, Yan, Ginhoux, Florent, Renia, Laurent, Urban, Britta C., and Nussenzweig, Michel C.

Subjects
T cells -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Biological response modifiers -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Dendritic cells -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Malaria -- Development and progression -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Innate sensing mechanisms trigger a variety of humoral and cellular events that are essential to adaptive immune responses. Here we describe an innate sensing pathway triggered by Plasmodium infection that [...]

Published
2013
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23. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

Author

Klein, Florian, Halper-Stromberg, Ariel, Horwitz, Joshua A., Gruell, Henning, Scheid, Johannes F., Bournazos, Stylianos, Mouquet, Hugo, Spatz, Linda A., Diskin, Ron, Abadir, Alexander, Zang, Trinity, Dorner, Marcus, Billerbeck, Eva, Labitt, Rachael N., Gaebler, Christian, Marcovecchio, Paola M., Incesu, Reha-Baris, Eisenreich, Thomas R., Bieniasz, Paul D., Seaman, Michael S., Bjorkman, Pamela J., Ravetch, Jeffrey V., Ploss, Alexander, and Nussenzweig, Michel C.

Subjects
Highly active antiretroviral therapy -- Protection and preservation -- Health aspects, Monoclonal antibodies -- Usage -- Health aspects, HIV infection -- Protection and preservation -- Health aspects -- Development and progression -- Drug therapy -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection (1,2). Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time (3,4). However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design (5-9). Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy (10-12), the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals., Treatment of HIV-1 infection was ineffective until antiretroviral drugs were applied in combination, permitting sustained suppression of viraemia (13,14). Despite this resounding success, the burden of daily medication, side effects [...]

Published
2012

27. Tissue CD14+CD8+T cells reprogrammed by myeloid cells and modulated by LPS

Author

Pallett, Laura J., Swadling, Leo, Diniz, Mariana, Maini, Alexander A., Schwabenland, Marius, Gasull, Adrià Dalmau, Davies, Jessica, Kucykowicz, Stephanie, Skelton, Jessica K., Thomas, Niclas, Schmidt, Nathalie M., Amin, Oliver E., Gill, Upkar S., Stegmann, Kerstin A., Burton, Alice R., Stephenson, Emily, Reynolds, Gary, Whelan, Matt, Sanchez, Jenifer, de Maeyer, Roel, Thakker, Clare, Suveizdyte, Kornelija, Uddin, Imran, Ortega-Prieto, Ana M., Grant, Charlotte, Froghi, Farid, Fusai, Giuseppe, Lens, Sabela, Pérez-del-Pulgar, Sofia, Al-Akkad, Walid, Mazza, Giuseppe, Noursadeghi, Mahdad, Akbar, Arne, Kennedy, Patrick T. F., Davidson, Brian R., Prinz, Marco, Chain, Benjamin M., Haniffa, Muzlifah, Gilroy, Derek W., Dorner, Marcus, Bengsch, Bertram, Schurich, Anna, and Maini, Mala K.

Abstract

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1–4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14highmyeloid cells in hepatic zone 2. CD14+CD8+T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+T cell profile can be recapitulated by the acquisition of membrane proteins—including the lipopolysaccharide receptor complex—from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut–liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+T cells with immunomodulatory ability.

Published
2023
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28. A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

Author

Skelton, Jessica Katy, Ortega‐Prieto, Ana Maria, Dorner, Marcus, Wellcome Trust, European Research Council, and Commission of the European Communities

Subjects
HLA CLASS-I, SCID MICE, Immunology, Transplantation, Heterologous, Mice, Transgenic, Review Article, BLT MICE, Adaptive Immunity, RAG-HU MICE, 1114 Paediatrics And Reproductive Medicine, Animals, Humans, Genetic Predisposition to Disease, Review Articles, Bone Marrow Transplantation, Science & Technology, T-CELL RESPONSES, HUMAN IMMUNE-SYSTEM, Hematopoietic Stem Cell Transplantation, MOUSE MODEL, COLONY-STIMULATING FACTOR, BARR-VIRUS INFECTION, Immunity, Innate, Immunity, Humoral, stem cell, immune system, Disease Models, Animal, Haematopoiesis, humanized mice, Phenotype, HEMATOPOIETIC STEM, 1107 Immunology, Virus Diseases, Host-Pathogen Interactions, Viruses, Life Sciences & Biomedicine, viral
Abstract

Summary Humanized mice are increasingly appreciated as an incredibly powerful platform for infectious disease research. The often very narrow species tropism of many viral infections, coupled with the sometimes misleading results from preclinical studies in animal models further emphasize the need for more predictive model systems based on human cells rather than surrogates. Humanized mice represent such a model and have been greatly enhanced with regards to their immune system reconstitution as well as immune functionality in the past years, resulting in their recommendation as a preclinical model by the US Food and Drug Administration. This review aims to give a detailed summary of the generation of human peripheral blood lymphocyte‐, CD34+ haematopoietic stem cell‐ and bone marrow/liver/thymus‐reconstituted mice and available improved models (e.g. myeloid‐ or T‐cell‐only mice, MISTRG, NSG‐SGM3). Additionally, we summarize human‐tropic viral infections, for which humanized mice offer a novel approach for the study of disease pathogenesis as well as future perspectives for their use in biomedical, drug and vaccine research.

Published
2018

32. Kinetics of Early Innate Immune Activation during HIV-1 Infection of Humanized Mice

Author

Skelton, Jessica Katy, Ortega-Prieto, Ana Maria, Kaye, Steve, Jimenez-Guardeño, Jose Manuel, Turner, Jane, Malim, Michael H., Towers, Greg J., Dorner, Marcus, and Kirchhoff, Frank

Subjects
Innate immunity, Human immunodeficiency virus, virus diseases, Humanized mouse
Abstract

Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence.

Published
2019
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33. OS070 - CD8+ T cell acquisition of the LPS receptor within the hepatic stroma shapes anti-viral/anti-tumour potential

Author

Pallett, Laura J., Diniz, Mariana, Swadling, Leo, Skelton, Jessica, Maini, Alexander, Davies, Jessica, Kucykowicz, Stephanie, Schmidt, Nathalie, Amin, Oliver E., Gill, Upkar, Burton, Alice, Sanchez, Jenifer, Fusai, Giuseppe, Lens, Sabela, Pérez-del-Pulgar, Sofía, Kennedy, Patrick, Davidson, Brian R., Haniffa, Muzlifah, Gilroy, Derek, Dorner, Marcus, Schurich, Anna, and Maini, Mala

Published
2022
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36. Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry

Author

Mazzon, Michela, primary, Ortega-Prieto, Ana, additional, Imrie, Douglas, additional, Luft, Christin, additional, Hess, Lena, additional, Czieso, Stephanie, additional, Grove, Joe, additional, Skelton, Jessica, additional, Farleigh, Laura, additional, Bugert, Joachim, additional, Wright, Edward, additional, Temperton, Nigel, additional, Angell, Richard, additional, Oxenford, Sally, additional, Jacobs, Michael, additional, Ketteler, Robin, additional, Dorner, Marcus, additional, and Marsh, Mark, additional

Published
2019
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38. Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry.

Author

Mazzon, Michela, Ortega-Prieto, Ana Maria, Imrie, Douglas, Luft, Christin, Hess, Lena, Czieso, Stephanie, Grove, Joe, Skelton, Jessica Katy, Farleigh, Laura, Bugert, Joachim J, Wright, Edward, Temperton, Nigel J., Angell, Richard, Oxenford, Sally, Jacobs, Michael, Ketteler, Robin, Dorner, Marcus, Marsh, Mark, Mazzon, Michela, Ortega-Prieto, Ana Maria, Imrie, Douglas, Luft, Christin, Hess, Lena, Czieso, Stephanie, Grove, Joe, Skelton, Jessica Katy, Farleigh, Laura, Bugert, Joachim J, Wright, Edward, Temperton, Nigel J., Angell, Richard, Oxenford, Sally, Jacobs, Michael, Ketteler, Robin, Dorner, Marcus, and Marsh, Mark

Abstract

Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy.

Published
2019

43. Oligonucleotide-Lipid Conjugates Forming G-Quadruplex Structures Are Potent and Pangenotypic Hepatitis C Virus Entry Inhibitors In Vitro and Ex Vivo

Author

Koutsoudakis, George, primary, Paris de León, Alexia, additional, Herrera, Carolina, additional, Dorner, Marcus, additional, Pérez-Vilaró, Gemma, additional, Lyonnais, Sébastien, additional, Grijalvo, Santiago, additional, Eritja, Ramon, additional, Meyerhans, Andreas, additional, Mirambeau, Gilles, additional, and Díez, Juana, additional

Published
2017
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45. Pediatric Epstein-Barr Virus Carriers With or Without Tonsillar Enlargement May Substantially Contribute to Spreading of the Virus

Author

Hug, Martina, Dorner, Marcus, Zucol Fröhlich, Franziska, Gysin, Claudine, Neuhaus, Diego, Nadal, David, Berger, Christoph, Hug, Martina, Dorner, Marcus, Zucol Fröhlich, Franziska, Gysin, Claudine, Neuhaus, Diego, Nadal, David, and Berger, Christoph

Abstract

Background. Human-to-human transmission of the persistent infection establishing Epstein-Barr virus (EBV) occurs via saliva. Tonsils act as important portal of entry and exit of EBV. The contagiousness of pediatric EBV carriers and the role played by tonsillar enlargement (TE) are not known. Methods. We compared EBV shedding in mouthwash samples from pediatric EBV carriers with or without TE to that in mouthwash samples from pediatric patients with infectious mononucleosis (IM), the symptomatic form of primary infection if delayed after the age of 5 years. EBV DNA was quantified by polymerase chain reaction, and contagiousness was assessed using the cord lymphocyte transformation assay. Results. EBV carriers with TE shed EBV DNA at an almost similar frequency (although in lower amounts) as pediatric patients with acute IM but more frequently (P ! .001) and in higher amounts (Pp.038) than EBV carriers without TE. EBV DNA levels in mouthwash samples from EBV carriers with TE mirrored levels in tonsils and gradually declined after tonsillectomy. Almost half of the mouthwash samples from pediatric EBV carriers contained infectious EBV. Conclusions. Pediatric EBV carriers-in particular, those with TE-may considerably contribute to the spreading of EBV in industrialized countries

Published
2017

46. Oligonucleotide-Lipid Conjugates Forming G-Quadruplex Structures Are Potent and Pangenotypic Hepatitis C Virus Entry Inhibitors In Vitro and Ex Vivo

Author

Koutsoudakis, George, Paris de León, Alexia, Herrera, Carolina, Dorner, Marcus, Pérez-Vilaró, Gemma, Lyonnais, Sébastien, Grijalvo, Santiago, Eritja Casadellà, Ramón, Meyerhans, Andreas, Mirambeau, Gilles, Díez, Juana, Koutsoudakis, George, Paris de León, Alexia, Herrera, Carolina, Dorner, Marcus, Pérez-Vilaró, Gemma, Lyonnais, Sébastien, Grijalvo, Santiago, Eritja Casadellà, Ramón, Meyerhans, Andreas, Mirambeau, Gilles, and Díez, Juana

Abstract

A hepatitis C virus (HCV) epidemic affecting HIV-infected men who have sex with men (MSM) is expanding worldwide. In spite of the improved cure rates obtained with the new direct-acting antiviral drug (DAA) combinations, the high rate of reinfection within this population calls urgently for novel preventive interventions. In this study, we determined in cell culture and ex vivo experiments with human colorectal tissue that lipoquads, G-quadruplex DNA structures fused to cholesterol, are efficient HCV pangenotypic entry and cell-to-cell transmission inhibitors. Thus, lipoquads may be promising candidates for the development of rectally applied gels to prevent HCV transmission.

Published
2017

48. Expanding the Host Range of Hepatitis C Virus through Viral Adaptation

Author

von Schaewen, Markus, Dorner, Marcus, Hueging, Kathrin, Foquet, Lander, Gerges, Sherif, Hrebikova, Gabriela, Heller, Brigitte, Bitzegeio, Julia, Doerrbecker, Juliane, Horwitz, Joshua A, Gerold, Gisa, Suerbaum, Sebastian, Rice, Charles M, Meuleman, Philip, Pietschmann, Thomas, Ploss, Alexander, von Schaewen, Markus, Dorner, Marcus, Hueging, Kathrin, Foquet, Lander, Gerges, Sherif, Hrebikova, Gabriela, Heller, Brigitte, Bitzegeio, Julia, Doerrbecker, Juliane, Horwitz, Joshua A, Gerold, Gisa, Suerbaum, Sebastian, Rice, Charles M, Meuleman, Philip, Pietschmann, Thomas, and Ploss, Alexander

Abstract

Hepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise the minimal set of human factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, species barriers can be overcome by adapting HCV to use the murine orthologues of these entry factors. We previously generated a murine tropic HCV (mtHCV or Jc1/mCD81) strain harboring three mutations within the viral envelope proteins that allowed productive entry into mouse cell lines. In this study, we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytes in vivo and in vitro Using a highly sensitive, Cre-activatable reporter, we demonstrate that mtHCV can enter mouse hepatocytes in vivo in the absence of any human cofactors. Viral entry still relied on expression of mouse CD81 and SCARB1 and was more efficient when mouse CD81 and OCLN were overexpressed. HCV entry could be significantly reduced in the presence of anti-HCV E2 specific antibodies, suggesting that uptake of mtHCV is dependent on viral glycoproteins. Despite mtHCV's ability to enter murine hepatocytes in vivo, we did not observe persistent infection, even in animals with severely blunted type I and III interferon signaling and impaired adaptive immune responses. Altogether, these results establish proof of concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. However, additional viral adaptations will likely be needed to increase the robustness of a murine model system for hepatitis C. IMPORTANCE: At least 150 million individuals are chronically infected with HCV and are at risk of developing serious liver disease. Despite the advent of effective antiviral therapy, the frequency of chronic carriers has only marginally decreased. A major roadblock in developing a vaccine that would prevent transmission is the scarcity of animal models that are susceptib

Published
2016
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49. Expanding the Host Range of Hepatitis C Virus through Viral Adaptation

Author

von Schaewen, Markus, primary, Dorner, Marcus, additional, Hueging, Kathrin, additional, Foquet, Lander, additional, Gerges, Sherif, additional, Hrebikova, Gabriela, additional, Heller, Brigitte, additional, Bitzegeio, Julia, additional, Doerrbecker, Juliane, additional, Horwitz, Joshua A., additional, Gerold, Gisa, additional, Suerbaum, Sebastian, additional, Rice, Charles M., additional, Meuleman, Philip, additional, Pietschmann, Thomas, additional, and Ploss, Alexander, additional

Published
2016
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50. A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease

Author

McDonald, Jacqueline U., primary, Kaforou, Myrsini, additional, Clare, Simon, additional, Hale, Christine, additional, Ivanova, Maria, additional, Huntley, Derek, additional, Dorner, Marcus, additional, Wright, Victoria J., additional, Levin, Michael, additional, Martinon-Torres, Federico, additional, Herberg, Jethro A., additional, and Tregoning, John S., additional

Published
2016
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