Lei Guo

Peking Union Medical College Hospital, Peping, Beijing, China

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Publications (9)67.15 Total impact

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    ABSTRACT: Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease in children and may be fatal. A vaccine against EV71 is needed. We conducted a randomized, double-blind, placebo-controlled phase 3 trial involving healthy children 6 to 71 months of age in Guangxi Zhuang Autonomous Region, China. Two doses of an inactivated EV71 vaccine or placebo were administered intramuscularly, with a 4-week interval between doses, and children were monitored for up to 11 months. The primary end point was protection against hand, foot, and mouth disease caused by EV71. A total of 12,000 children were randomly assigned to receive vaccine or placebo. Serum neutralizing antibodies were assessed in 549 children who received the vaccine. The seroconversion rate was 100% 4 weeks after the two vaccinations, with a geometric mean titer of 170.6. Over the course of two epidemic seasons, the vaccine efficacy was 97.4% (95% confidence interval [CI], 92.9 to 99.0) according to the intention-to-treat analysis and 97.3% (95% CI, 92.6 to 99.0) according to the per-protocol analysis. Adverse events, such as fever (which occurred in 41.6% of the participants who received vaccine vs. 35.2% of those who received placebo), were significantly more common in the week after vaccination among children who received the vaccine than among those who received placebo. The inactivated EV71 vaccine elicited EV71-specific immune responses and protection against EV71-associated hand, foot, and mouth disease. (Funded by the National Basic Research Program and others; ClinicalTrials.gov number, NCT01569581.).
    New England Journal of Medicine 02/2014; 370(9):829-37. · 54.42 Impact Factor
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    ABSTRACT: During HSV-1 infection, the viral UL31 protein forms a complex with the UL34 protein at the cellular nuclear membrane, where both proteins play important roles in the envelopment of viral nucleocapsids and their egress into the cytoplasm. To characterize the mechanism of HSV-1 nucleocapsid egress, we screened host proteins to identify proteins that interacted with UL31 via yeast two-hybrid analysis. Transmembrane protein 140 (TMEM140), was identified and confirmed to bind to and co-localize with UL31 during viral infection. Further studies indicated that TMEM140 inhibits HSV-1 proliferation through selectively blocking viral nucleocapsid egress during the viral assembly process. The blockage function of TMEM140 is mediated by impeding the formation of the UL31–UL34 complex due to competitive binding to UL31. Collectively, these data suggest the essentiality of the UL31–UL34 interaction in the viral nucleocapsid egress process and provide a new anti-HSV-1 strategy in viral assembly process of nucleocapsid egress.
    Virology. 01/2014; s 464–465:1–10.
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    ABSTRACT: Viral microRNAs are one component of the RNA interference phenomenon generated during viral infection. They were first identified in the Herpesviridae family, where they were found to regulate viral mRNA translation. In addition, prior work has suggested that Kaposi's sarcoma-associated herpesvirus (KSHV) is capable of regulating cellular gene transcription by miRNA. We demonstrate that a miRNA, hsv1-mir-H27, encoded within the genome of herpes simplex virus 1 (HSV-1), targets the mRNA of the cellular transcriptional repressor Kelch-like 24 (KLHL24) that inhibits transcriptional efficiency of viral immediate-early and early genes. The viral miRNA is able to block the expression of KLHL24 in cells infected by HSV-1. Our discovery reveals an effective viral strategy for evading host cell defenses and supporting the efficient replication and proliferation of HSV-1.
    Science China. Life sciences 03/2013; · 2.02 Impact Factor
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    ABSTRACT: Enterovirus 71 (EV71), a major causative agent of hand-foot-and-mouth disease (HFMD), causes outbreaks among children in the Asia-Pacific region. A vaccine is urgently needed. Based on successful pre-clinical work, phase I and II clinical trials of an inactivated EV71 vaccine, which included the participants of 288 and 660 respectively, have been conducted. In the present study, the immune response and the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) of 30 infants (6 to 11 months) immunized with this vaccine or placebo and consented to join this study in the phase II clinical trial were analyzed. The results showed significantly greater neutralizing antibody and specific T cell responses in vaccine group after two inoculations on days 0 and 28. Additionally, more than 600 functional genes that were up- or down-regulated in PBMCs were identified by the microarray assay, and these genes included 68 genes associated with the immune response in vaccine group. These results emphasize the gene expression profile of the immune system in response to an inactivated EV71 vaccine in humans and confirmed that such an immune response was generated as the result of the positive mobilization of the immune system. Furthermore, the immune response was not accompanied by the development of a remarkable inflammatory response.CLINICAL TRIAL REGISTRATION: NCT01391494 and NCT01512706.
    PLoS ONE 01/2013; 8(1):e54451. · 3.53 Impact Factor
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    ABSTRACT: ICP22 is a multifunctional herpes simplex virus 1 (HSV-1) immediate early protein that functions as a general repressor of a subset of cellular and viral promoters in transient expression systems. Although the exact mechanism of repression remains unclear, this protein induces a decrease in RNA polymerase II Serine 2 (RNAPII Ser-2) phosphorylation, which is critical for transcription elongation. To characterize the mechanism of transcriptional repression by ICP22, we established an in vivo transient expression reporter system. We found that ICP22 inhibits transcription of the HSV-1 α, β and γ gene promoters. The viral tegument protein VP16, which plays vital roles in initiation of viral gene expression and viral proliferation, can overcome the inhibitory effect of ICP22 on α-gene transcription. Further immunoprecipitation studies indicated that both ICP22 and VP16 bind to positive transcription elongation factor b (P-TEFb) and form a complex with it in vivo. We extended this to show that P-TEFb regulates transcription of the viral α-gene promoters and affects transcriptional regulation of ICP22 and VP16 on the α-genes. Additionally, ChIP assays demonstrated that ICP22 blocks the recruitment of P-TEFb to the viral promoters, while VP16 reverses this blocking effect by recruiting P-TEFb to the viral α-gene promoters through recognition of the TAATGARAT motif. Taken together, our results suggest that ICP22 interacts with and blocks the recruitment of P-TEFb to viral promoter regions, which inhibits transcription of the viral gene promoters. The transactivator VP16 binds to and induces the recruitment of P-TEFb to viral α-gene promoters, which counteracts the transcriptional repression of ICP22 on α-genes by recruiting p-TEFb to the promoter region.
    PLoS ONE 01/2012; 7(9):e45749. · 3.53 Impact Factor
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    ABSTRACT: In light of the scarcity of reports on the interaction between HSV-1 nucleocapsid protein UL25 and its host cell proteins, the purpose of this study is to use yeast two-hybrid screening to search for cellular proteins that can interact with the UL25 protein. C9orf69, a protein of unknown function was identified. The interaction between the two proteins under physiological conditions was also confirmed by biological experiments including co-localization by fluorescence and immunoprecipitation. A preliminary study of the function of C9orf69 showed that it promotes viral proliferation. Further studies showed that C9orf69 did not influence viral multiplication efficiency by transcriptional regulation of viral genes, but indirectly promoted proliferation via interaction with UL25.
    Virologica Sinica 06/2011; 26(3):171-80.
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    ABSTRACT: The protein encoded by HSRG1 (HSV-1 stimulation-related gene 1) is a virally induced protein expressed in HSV-1-infected cells. We have already reported that HSRG1 is capable of interacting with transcriptional regulator proteins. To further analyze the effects of HSRG1 on the regulation of viral gene transcription, we expressed the HSRG1 protein in transfected cells and found that it postpones the proliferation of HSV-1. CAT (chloramphenicol acetyltransferase) assays also revealed that HSRG1 reduces transcription from HSV-1 promoters. Yeast two-hybrid and immunoprecipitation assays indicated that HSRG1 interacts with Cyclin T2, the regulatory subunit of P-TEFb, which is required for transcription elongation by RNA Pol II (RNAP II), and that amino acid residues 1-420 in Cyclin T2 are important for binding with HSRG1. Fluorescence assays suggested that the cellular localizations of those two proteins are influenced by their interaction. Further analyses with CAT assays revealed that HSRG1 inhibits the transcriptional activation by Cyclin T2 of viral promoters. Our results suggested that the inhibitory effects of HSRG1 on viral replication and proliferation are probably induced by its binding to Cyclin T2. Therefore, it is likely that HSRG1 inhibits viral gene transcriptional elongation by interacting with Cyclin T2.
    Science China. Life sciences 04/2011; 54(4):359-65. · 2.02 Impact Factor
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    ABSTRACT: Herpes Simplex Virus 1 (HSV1) is capable of inducing two forms of infection in individuals, and the establishment of which type of infection occurs is linked to the transcriptional activation of viral alpha genes. One of the HSV1 alpha genes, ICP22, is known to have multiple functions during virus replication, but its distinct roles are still unclear. This study showed that ICP22 functions as a general repressor for certain viral and cellular promoters, and this transcriptional repression by ICP22 is independent of the specific upstream promoter element, as shown using the CAT enzyme assay system. Further work also found that VP16 interfered with ICP22 mediated transcriptional repression of the viral alpha4 gene, through interactions with specific elements upstream of the alpha4 gene promoter. These findings support the possibility that ICP22 and VP16 control transcription of HSV1alpha genes in a common pathway for the establishment of either viral lytic or latent infections.
    Science in China Series C Life Sciences 05/2009; 52(4):344-51. · 1.61 Impact Factor
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    ABSTRACT: An interaction between the HSV-1 UL25 capsid protein and cellular microtubule-associated protein was found using a yeast two-hybrid screen and β-D-galactosidase activity assays. Immunofluorescence microscopy of the UL25 protein demonstrated its co-localization with cellular microtubule-associated protein in the plasma membrane. Further investigations with deletion mutants suggest that UL25 is likely to have a function in the nucleus.
    Virologica Sinica 06/2008; 23(3):211-217.

Publication Stats

38 Citations
67.15 Total Impact Points

Institutions

  • 2012–2014
    • Peking Union Medical College Hospital
      Peping, Beijing, China
  • 2008–2013
    • Chinese Academy of Medical Sciences
      Peping, Beijing, China
  • 2011
    • China Academy of Chinese Medical Sciences
      • Institute of Medical Biology
      Peping, Beijing, China