Hepatitis C remains a global epidemic. At least 130 million individuals suffer from chronic hepatitis C, which is caused by hepatitis C virus (HCV) - a positive sense, single-stranded RNA virus of the Flaviviridae family. HCV has a high propensity for establishing chronic infection. If untreated chronic HCV carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Antiviral treatment is only partially effective, costly and often poorly tolerated. A prophylactic or therapeutic vaccine for HCV does not exist. Development of more effective therapies and vaccines has been hampered by the lack of a suitable small animal model.! Building on our previous observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive for HCV entry in vitro, we attempted murine humanization via a genetic approach. We demonstrated that expression of the two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We provide comprehensive preliminary data demonstrating that a combination of innate and adaptive immune responses restricts persistent HCV replication in these mice. We demonstrate that blunting antiviral immunity in mice expressing human CD81 and OCLN results in low level, viremia over several weeks. This observation provides critical evidence for the feasibility of adapting HCV to replicate efficientlyin conditioned inbred mouse strain. We now propose to systematically overcome additional blocks to interspecies growth of the HCV by exploiting HCV's remarkable genetic plasticity. Our studies will ultimately lead to a fully immunocompetent mouse model for HCV infection, which we will use to study HCV-associated liver disease. An inbred mouse model that supports the entire HCV life-cycle opens unprecedented opportunities to genetically dissect HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug and vaccine candidates. !

Public Health Relevance

Highly efficacious, cost-effective therapies including a vaccine for hepatitis C virus (HCV), a widespread agent of severe liver disease, remain elusive. We propose to optimize new animal models that will speed the study of hepatitis C in vivo and provide a test platform for antiviral therapies. !

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Koshy, Rajen
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Princeton University
Schools of Arts and Sciences
United States
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Ding, Qiang; Gaska, Jenna M; Douam, Florian et al. (2018) Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease. Proc Natl Acad Sci U S A 115:E6310-E6318
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Douam, Florian; Soto Albrecht, Yentli E; Hrebikova, Gabriela et al. (2017) Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo. MBio 8:
Douam, Florian; Ding, Qiang; Ploss, Alexander (2016) Recent advances in understanding hepatitis C. F1000Res 5:
Shirvani-Dastgerdi, Elham; Schwartz, Robert E; Ploss, Alexander (2016) Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. Curr Opin Virol 20:1-10
von Schaewen, Markus; Hrebikova, Gabriela; Ploss, Alexander (2016) Generation of Human Liver Chimeric Mice for the Study of Human Hepatotropic Pathogens. Methods Mol Biol 1438:79-101
Winer, Benjamin Y; Ploss, Alexander (2016) Breaking the species barrier for hepatitis delta virus. Hepatology 63:334-6

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