Publication Date:
2011-06-10
Description:
Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159410/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159410/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dorner, Marcus -- Horwitz, Joshua A -- Robbins, Justin B -- Barry, Walter T -- Feng, Qian -- Mu, Kathy -- Jones, Christopher T -- Schoggins, John W -- Catanese, Maria Teresa -- Burton, Dennis R -- Law, Mansun -- Rice, Charles M -- Ploss, Alexander -- F32DK081193/DK/NIDDK NIH HHS/ -- F32DK082155/DK/NIDDK NIH HHS/ -- R01 AI071084/AI/NIAID NIH HHS/ -- R01 AI071084-04/AI/NIAID NIH HHS/ -- R01 AI072613/AI/NIAID NIH HHS/ -- R01 AI072613-05/AI/NIAID NIH HHS/ -- R01 AI079031/AI/NIAID NIH HHS/ -- R01 AI079031-04/AI/NIAID NIH HHS/ -- R01 DK085713/DK/NIDDK NIH HHS/ -- R01 DK085713-03/DK/NIDDK NIH HHS/ -- R01AI071084/AI/NIAID NIH HHS/ -- R01AI072613/AI/NIAID NIH HHS/ -- R01AI079031/AI/NIAID NIH HHS/ -- RC1 DK087193/DK/NIDDK NIH HHS/ -- RC1 DK087193-02/DK/NIDDK NIH HHS/ -- RC1DK087193/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Jun 8;474(7350):208-11. doi: 10.1038/nature10168.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654804" target="_blank"〉PubMed〈/a〉
Keywords:
Adenoviridae/genetics/physiology
;
Animals
;
Antibodies, Blocking/immunology
;
Antigens, CD/genetics/metabolism
;
Antigens, CD81
;
Cells, Cultured
;
Claudin-1
;
*Disease Models, Animal
;
Genotype
;
Hepacivirus/genetics/metabolism/*physiology
;
Hepatitis C/*genetics/*virology
;
Hepatocytes/cytology/*metabolism/*virology
;
Humans
;
Immunization, Passive
;
Membrane Proteins/genetics/metabolism
;
Mice
;
Receptors, Virus/genetics/metabolism
;
Scavenger Receptors, Class B/genetics/metabolism
;
Transfection
;
Viral Tropism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
