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      Hepatitis C Virus Vaccine: Challenges and Prospects

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          Abstract

          The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated.

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          Most cited references158

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          Binding of hepatitis C virus to CD81.

          Chronic hepatitis C virus (HCV) infection occurs in about 3 percent of the world's population and is a major cause of liver disease. HCV infection is also associated with cryoglobulinemia, a B lymphocyte proliferative disorder. Virus tropism is controversial, and the mechanisms of cell entry remain unknown. The HCV envelope protein E2 binds human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Binding of E2 was mapped to the major extracellular loop of CD81. Recombinant molecules containing this loop bound HCV and antibodies that neutralize HCV infection in vivo inhibited virus binding to CD81 in vitro.
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            The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus.

            We discovered that the hepatitis C virus (HCV) envelope glycoprotein E2 binds to human hepatoma cell lines independently of the previously proposed HCV receptor CD81. Comparative binding studies using recombinant E2 from the most prevalent 1a and 1b genotypes revealed that E2 recognition by hepatoma cells is independent from the viral isolate, while E2-CD81 interaction is isolate specific. Binding of soluble E2 to human hepatoma cells was impaired by deletion of the hypervariable region 1 (HVR1), but the wild-type phenotype was recovered by introducing a compensatory mutation reported previously to rescue infectivity of an HVR1-deleted HCV infectious clone. We have identified the receptor responsible for E2 binding to human hepatic cells as the human scavenger receptor class B type I (SR-BI). E2-SR-BI interaction is very selective since neither mouse SR-BI nor the closely related human scavenger receptor CD36, were able to bind E2. Finally, E2 recognition by SR-BI was competed out in an isolate-specific manner both on the hepatoma cell line and on the human SR-BI-transfected cell line by an anti-HVR1 monoclonal antibody.
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              HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.

              Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.
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                Author and article information

                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                17 February 2020
                March 2020
                : 8
                : 1
                : 90
                Affiliations
                [1 ]School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; richard.urbanowicz@ 123456nottingham.ac.uk (R.A.U.); alex.tarr@ 123456nottingham.ac.uk (A.W.T.); jonathan.ball@ 123456nottingham.ac.uk (J.K.B.)
                [2 ]NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
                [3 ]Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
                Author notes
                Author information
                https://orcid.org/0000-0002-8638-4628
                https://orcid.org/0000-0002-2461-4993
                https://orcid.org/0000-0003-1009-0823
                Article
                vaccines-08-00090
                10.3390/vaccines8010090
                7157504
                32079254
                9fc1ce88-3688-40fe-b7f9-80a2783b27e1
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 December 2019
                : 04 February 2020
                Categories
                Review

                hepatitis c virus,vaccines,neutralising antibodies,animal models,immune responses

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