Jie Lu

Shanghai Jiao Tong University, Shanghai, Shanghai Shi, China

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Publications (7)39.77 Total impact

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    ABSTRACT: To investigate whether IPS1 polymorphisms affect peginterferon alpha (PEG-IFN) efficacy in chronic hepatitis B (CHB) patients using a tag- single nucleotide polymorphism (SNP) approach.
    Infection Genetics and Evolution 01/2015; 37. DOI:10.1016/j.meegid.2015.01.013 · 3.26 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is a human pathogen that can evade host immunity to cause persistent infection, leading to liver cirrhosis and hepatocellular carcinoma. The transfected 3'UTR of HCV genomic RNA can be recognized by host protein RIG-I to activate interferon production in hepatocytes. However, it is difficult to demonstrate the RIG-I mediated sensing of HCV genomic RNA in the context of HCV infection because HCV encoded-NS3-4A protease can inactivate MAVS, a critical adaptor protein in interferon signaling. Our aim was to identify the viral sensor that triggers interferon response in hepatocytes during HCV infection. We generated a hepatic cell line that stably express mutant MAVS resistant to the NS3-4A cleavage. This cell line allowed us to investigate interferon signaling pathway in the context of HCV infection. By using the knockdown and knockout technology together with biochemical approaches, we were able to identify the actual viral sensor in hepatocytes during HCV infection. We showed that HCV infection induced robust interferon response in the cells expressing MAVS resistant to the NS3-4A cleavage. Unexpectedly, the interaction between HCV's 3'UTR and RIG-I seemed to play a minor role in this activation, while another helicase MDA5 played a more important role in sensing HCV infection to trigger interferon response. Our data demonstrate that MDA5 recognizes HCV to initiate host innate immune response during HCV infection. This study provides insight into how host senses HCV to initiate innate immunity during HCV infection. Copyright © 2014. Published by Elsevier B.V.
    Journal of Hepatology 11/2014; 62(4). DOI:10.1016/j.jhep.2014.11.007 · 10.40 Impact Factor
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    ABSTRACT: HCV infection is a leading cause of chronic liver diseases. The progress in HCV field was greatly enhanced by constructing infectious cDNA clone of JFH-1. Since then, JFH-1-based intra- and inter-genotypic recombinants were developed and allowed the study of vaccines and antiviral inhibitors for all genotypes. Only until recently, highly efficient HCV culture systems have been established by using consensus sequence-based clones. In this study, we developed a novel strategy to construct infectious HCV cDNA clone by combining functional screening of sequences directly from a genotype 2a clinical isolate (PR63) and cell culture adaptation. Using JFH-1 cDNA as the starting backbone, we sequentially replaced the JFH-1 fragments with a sequence from the pools of PR63 sequences. Through engineering adaptive mutations that improve HCV infectivity, we finally established a full-length cell culture-derived infectious clone of PR63, named PR63cc, which could efficiently produce virus particles in Huh7 derived cells, with peak titers of 1.6×10(5) ffu/mL. The PR63cc could be neutralized by an anti-E2 antibody and inhibited by antiviral agents, but appeared more resistant to an NS5A inhibitor than JFH-1. In summary: we developed a new approach to construct infectious HCV cDNA clone that can produce viruses efficiently in cell culture. This approach could be applied to other viral isolates, with potential implications for individualized treatments of HCV patients.
    Journal of Virology 11/2013; DOI:10.1128/JVI.02929-13 · 4.65 Impact Factor
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    ABSTRACT: HCV genotype is a major determinant of clinical outcome, and GT1b HCV infection is the most difficult to treat and also the predominant genotype in East Asia and Europe. We developed 1b/JFH-1 inter-genotypic recombinants containing the structural genes (Core, E1, E2), p7 and the 1stTMD of NS2 directly from GT1b clinical isolates. Through a cloning selection strategy, we obtained 4 functional clones from 3 cases of GT1b patients' sera, which could produce infectious viruses in Huh7.5.1 cells. Sequencing analysis of recovered viruses from serial passage and reverse genetics revealed that adaptive mutations in the GT1b-originated region were enough for the enhancement of infectivity. A monoclonal antibody to E2 and original patient sera could efficiently block 3 of the viruses (26C3mt, 52B6mt and 79L9) while had little effect on 26C6mt viruses. The availability of 1b/JFH-1 chimeric viruses will be important for studies of isolate-specific neutralization and useful in evaluating antiviral therapies.
    Virology 05/2013; 443(1). DOI:10.1016/j.virol.2013.04.030 · 3.28 Impact Factor
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    ABSTRACT: BACKGROUND AND AIMS: Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrohsis and hepatocellular carcinoma. Majority of acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses. METHODS AND RESULTS: We screened HCV encoded proteins for their activities to suppress the interferon signaling. We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. Co-immunoprecipitation and confocal microscopic analyses showed that NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1. CONCLUSIONS: In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
    Journal of Hepatology 03/2013; 59(1). DOI:10.1016/j.jhep.2013.03.019 · 10.40 Impact Factor
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    ABSTRACT: Type I interferons (IFNs), including IFN-α, -β, and -ω, play a critical role in innate immune responses against viral infection. IFN-λ, including IL-29, IL-28A, and IL-28B, recently identified as a new subfamily of IFN named type III IFN, has also been demonstrated to suppress virus replication in vitro and in vivo. However, the molecular mechanisms that regulate the induction of type III IFNs during viral infection remain elusive. Here, we demonstrate that IL-28 (IFN-λ 2/3) IFN production, similar to type I IFN, represents a primary and direct host response to HCV genomic RNA transfection. IL-28 (IFN-λ2/3) induction by HCV genomic RNA was dependent upon the activation of NF-κB and IRF3. We identified a minimal IL-28 promoter region consisting of putative NF-κB and IRF3-binding sites. Furthermore, we showed that HCV infection can inhibit HCV genomic RNA-induced IL-28 expression, and that the viral NS3/4A protease activity was responsible for this inhibitory effect. Our results present important evidence for the control of type III IFN response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
    European Journal of Immunology 09/2012; 42(9):2374-82. DOI:10.1002/eji.201242388 · 4.52 Impact Factor
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    ABSTRACT: The efficiencies of IFN-α based therapy in chronic genotype 1b HCV patients are still unsatisfied to date. The mechanisms underlining treatment failure remain unclear and controversial. To investigate HCV sequence evolution in unsuccessfully treated genotype 1b patients before, during and after the therapy, full-length open-reading-frame of HCV genomes at week 0, week 48 and year 5 in one breakthrough and one nonresponse patients were amplified by reverse transcription (RT)-nested-PCR and sequenced. Mutations were scored and analyzed according to their locations in the HCV genome. HCV sequences in the breakthrough patient displayed significantly more mutations during the one-year therapy than that in the nonresponse patient, with p7 and NS2 encoding regions having the highest mutation rates. Most of the mutations selected during the therapy phase in the breakthrough patient were maintained and few new mutations arose in the four-year post-therapy phase, suggesting these mutations might not compromise viral fitness. Altogether our data suggest that mutations occurred during the therapy phase in the breakthrough patient are likely driven by the action of interferon and ribavirin, and these mutations may have important effects on the responses to interferon based therapy in genotype 1b HCV patients.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 12/2010; 11(2):382-90. DOI:10.1016/j.meegid.2010.11.011 · 3.26 Impact Factor