Unraveling hepatitis C virus replication from genome to function

Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Nature (Impact Factor: 41.46). 09/2005; 436(7053):933-8. DOI: 10.1038/nature04077
Source: PubMed


Since the discovery of the hepatitis C virus over 15 years ago, scientists have raced to develop diagnostics, study the virus and find new therapies. Yet virtually every attempt to dissect this pathogen has met with roadblocks that impeded progress. Its replication was restricted to humans or experimentally infected chimpanzees, and efficient growth of the virus in cell culture failed until very recently. Nevertheless hard-fought progress has been made and the first wave of antiviral drugs is entering clinical trials.

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    • "Countries in Africa and Asia have the highest infection rates with estimated regional prevalences of 1.6–4.5% (Hanafiah et al., 2013). HCV is a small, positive-sense, ssRNA virus in the genus Hepacivirus, family Flaviviridae (Choo et al., 1991; Lindenbach & Rice, 2005). The HCV genome is *9600 nt and encodes a single polyprotein with the following gene order: 59-core–envelope (E1–E2)–non-structural proteins [NS1(p7)–NS2–NS3–NS4A–NS4B–NS5A–NS5B]-39. "
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    ABSTRACT: Hepatitis C virus (HCV) is classified into 7 genotypes based on genetic diversity and most genotypes have been found in Africa. Infections with HCV genotype 2 (HCV2) are most prevalent in West Africa, and it was suggested that HCV2 originated in West Africa. To better understand the evolutionary epidemiology of HCV2 in Africa, we examined new NS5b sequences of HCV2 strains obtained from Côte d'Ivoire, Ghana and Nigeria sequenced in this laboratory with those available from West, North and Central Africa. Bayesian phylogeographic analysis using a discrete trait model showed that Ghana is the most likely geographic region for origin of HCV2. Spread of HCV2 from Ghana does not appear to be through diffusion to adjacent countries along the coast. Rather, it was transmitted from Ghana to many distant countries in Africa, suggesting that certain routes of geographic dissemination were historically more efficient than mere proximity and that the HCV2 epidemic history in West Africa is extremely complex.
    Journal of General Virology 04/2015; 96(8). DOI:10.1099/vir.0.000153 · 3.18 Impact Factor
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    • "It possesses an approximately 9.6 kb positive sense RNA genome that is translated as a single polypeptide approximately 3000 amino acids in length (Baron, 1996; Lindenbach and Rice, 2005). It is subsequently proteolytically cleaved into 10 viral proteins including the structural proteins Core, E1, E2, and the integral membrane ion channel p7, as well as the non-structural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B (Lindenbach and Rice, 2005). The 5 0 noncoding region (NCR) of the viral genome possesses an internal ribosomal entry site (IRES) (Wang et al., 1993), a cis-acting element found in some host RNA transcripts as well as in viruses that allows ribosomal translation initiation to occur internally within a transcript in lieu of 5 0 cap dependent translation (Pacheco and Martinez-Salas, 2010). "
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    ABSTRACT: We previously identified the NS5A/HSP70 binding site to be a hairpin moiety at C-terminus of NS5A domain I and showed a corresponding cyclized polyarginine-tagged synthetic peptide (HCV4) significantly blocks virus production. Here, sequence comparison confirmed five residues to be conserved. Based on NS5A domain I crystal structure, Phe171, Val173, and Tyr178 were predicted to form the binding interface. Substitution of Phe171 and Val173 with more hydrophobic unusual amino acids improved peptide antiviral activity and HSP70 binding, while similar substitutions at Tyr178 had a negative effect. Substitution of non-conserved residues with arginines maintained antiviral activity and HSP70 binding and dispensed with polyarginine tag for cellular entry. Peptide cyclization improved antiviral activity and HSP70 binding. The cyclic retro-inverso analog displayed the best antiviral properties. FTIR spectroscopy confirmed a secondary structure consisting of an N-terminal beta-sheet followed by a turn and a C-terminal beta-sheet. These peptides constitute a new class of anti-HCV compounds. Copyright © 2014 Elsevier Inc. All rights reserved.
    Virology 11/2014; 475C:46-55. DOI:10.1016/j.virol.2014.10.011 · 3.32 Impact Factor
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    • "Chronic HCV infection becomes one of the most common causes of chronic hepatitis, and other severe liver diseases including steatosis, cirrhosis and hepatocellular carcinoma (HCC)3. Much progress has been made on HCV biology4, and how immune evasion leads to HCV persistent infection5,6. However, understanding of HCV infection and pathogenesis is still hampered by its narrow host range, mostly restricted to humans and chimpanzees. "
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    ABSTRACT: The majority of hepatitis C virus (HCV) infection develops chronic infection, which causes steatosis, cirrhosis and hepatocellular carcinoma. However, understanding HCV chronicity and pathogenesis is hampered by its narrow host range, mostly restricted to human and chimpanzee. Recent endeavour to infect a variety of humanized mice has not been able to achieve persistent HCV infection unless the essential innate immune responsive genes are knocked out. Nevertheless, such immune-compromised humanized mice still lacked HCV infection-induced hepatopathogenesis. Here we report that transgenic mice in ICR background harboring both human CD81 and occludin genes (C/O(Tg)) are permissive to HCV infection at a chronicity rate comparable to humans. In this mouse model, HCV accomplishes its replication cycle, leading to sustained viremia and infectivity for more than 12 months post infection with expected fibrotic and cirrhotic progression. Host factors favorable for HCV replication, and inadequate innate immune-response may contribute to the persistence. Lastly, NS3/4 protease inhibitor telaprevir can effectively inhibit de novo RNA synthesis and acute HCV infection of C/O(Tg) mice. Thus, chronic HCV infection with complete replication cycle and hepatopathologic manifestations is recapitulated, for the first time, in immune-competent mice. This model will open a new venue to study the mechanisms of chronic hepatitis C and develop better treatments.Cell Research advance online publication 26 August 2014; doi:10.1038/cr.2014.116.
    Cell Research 08/2014; 24(9). DOI:10.1038/cr.2014.116 · 12.41 Impact Factor
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