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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Available from: Brett Lindenbach, Oct 10, 2015
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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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    • "Among the 185 million infected people worldwide, self-clearance occurs within 20–40% of the patients (Chen et al., 2002; Negro, 2013). Chronic carriers are at risk of liver cirrhosis and HCC (Lindenbach and Rice, 2005). There is no vaccine available against HCV because of high viral genomic variations and rapid mutation rates leading to swarms of closely related viral quasispecies to escape adaptive immunity (Abrignani et al., 1999; Prince and Shata, 2001). "
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    ABSTRACT: Intra venous drug users (IVDUs) are at high risk for hepatitis C virus (HCV) infection owing to their high rate of drug abuses. The north-eastern part of India has a high prevalence of IVDUs with Manipur being the worst hit state. The aim of the study was to document the molecular epidemiology, the patterns of HCV transmission, genomic variation and recombination events within HCV genome among IVDUs of Manipur, India. 91 anti-HCV sero-reactive blood samples were collected from IVDUs in Manipur. The samples were processed for RNA extraction, nested RT-PCR, sequencing and quantitative viral RNA estimation. Phylogeographic analysis of the sequenced core and NS5B regions of HCV genome was performed to determine the probable transmission route and recombinant HCV strains. 83 out of 91 anti-HCV seropositive samples were RNA positive (91.20%) based on 5’UTR of HCV genome by nested RT-PCR. Of the RNA positive samples, 73 paired partial core and NS5B gene were sequenced. Three major genotype and eight subtypes were detected while no recombinant strains were found. Individuals with genotype 1 had the mean viral load (5.94±0.705log10IU/ml) followed by genotype 3 (4.91±0.49log10IU/ml) and 6 (3.96±0.32log10IU/ml). The viral load was statistically significant among the male individuals at 4.822±1.36log10IU/ml compared to 4.767±0.49log10IU/ml for females (t=3.249, p<0.005). The phylogeographic results indicated 3b, 6h originated from Vietnam, 1a had Indian origin, 3a, 6k originated from southern China while 1b originated from Myanmar respectively. The incidence of eight different subtypes in Manipur reflects the transmission of these strains from the “Golden triangle” drug trafficking regions. Sequence analysis confirmed the transmission routes of HCV, which is linked to China and Vietnam for the newly emergent genotype 6 in north-eastern India.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 06/2014; 24. DOI:10.1016/j.meegid.2014.03.008 · 3.02 Impact Factor
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