YEARS

2012-2014

AUTHORS

Luis Martinez-Sobrido

TITLE

Single-cycle Infectious Candid#1 to Study Hemorrhagic Fever New World Arenavirus

ABSTRACT

DESCRIPTION (provided by applicant): Arenaviruses include several causative agents of Hemorrhagic Fever (HF) disease in humans that are associated with high morbidity and significant mortality. Moreover, weaponized forms of arenaviruses pose a serious threat as agents of bioterrorism. Public health concerns posed by arenaviruses are aggravated by the lack of licensed vaccines and by current anti-arenavirus therapy limited to the off-label use of ribavirin, which is only partially effective and often associated with severe side effects. Limitations in the study of HF arena-viruses include the manipulation of live forms of these agents under BioSafety Level (BSL) 4 laboratories and the requirement of secondary assays for detection of the virus. Development of valid single-cycle infectious surrogates that allow the study of HF arenavirus under less-strict BSL2 facilities and that express a reporter gene for easy viral detection will facilitate the identification of prophylactic and therapeutic strategies using safe, sensitive and specific screening assays compatible with High Throughput Screening (HTS) technologies. Furthermore, they will also represent promising vaccine approaches that circumvent concerns about potential out-of-control replication of attenuated vaccine strains that might lead to disease. Recently, we have described, for the first time, the generation of a single-cycle infectious, reporter-expressing, Old World Lymphocytic Choriomeningitis Virus (LCMV) where we replaced the viral glycoprotein (GP) with a reporter green fluorescent protein (GFP), rLCMV?GP/GFP. Infectious virus was achieved via genetic trans- complementation with cell lines constitutively expressing LCMV GP. This system allowed us to study multiple aspects of the virus and to develop screening assays for detection and quantification of neutralizing antibodies and identification of viral inhibitors. We were also able to extend our work to Lassa virus (LASV), an HF member of the Old World arenavirus, by generating LASV GP-expressing cell lines and LASV GP-pseudotyped rLCMV?GP/GFP. Since Old World and New World arena-viruses differ in their reservoirs, cellular receptor use for viral entry, and RNA genome composition, the development of valid surrogates to study New World arenavirus is imperative to provide researchers a way to study all aspects of the virus biology, to identify antivirals, and to develop vaccines against New World arenaviruses under less strict biosafety laboratories. In this application we propose to expand our recently described technology to the study of New World arenavirus by generating a single-cycle infectious, reporter-expressing, attenuated vaccine strain Candid#1 (rCan?GP/GFP).

FUNDED PUBLICATIONS

  • D471G mutation in LCMV-NP affects its ability to self-associate and results in a dominant negative effect in viral RNA synthesis.
  • Generation of recombinant arenavirus for vaccine development in FDA-approved Vero cells.
  • Arenavirus Genome Rearrangement for the Development of Live Attenuated Vaccines.
  • The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant?
  • Inhibition of arenavirus by A3, a pyrimidine biosynthesis inhibitor.
  • The human cytomegalovirus UL26 protein antagonizes NF-κB activation.
  • Protection against lethal influenza with a viral mimic.
  • Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.
  • Development of live-attenuated arenavirus vaccines based on codon deoptimization.
  • Arenavirus reverse genetics for vaccine development.
  • Induction of CD8 T cell heterologous protection by a single dose of single-cycle infectious influenza virus.
  • Influenza A and B virus intertypic reassortment through compatible viral packaging signals.
  • Cytomegalovirus-mediated activation of pyrimidine biosynthesis drives UDP-sugar synthesis to support viral protein glycosylation.
  • Lymphocytic Choriomeningitis Virus Differentially Affects the Virus-Induced Type I Interferon Response and Mitochondrial Apoptosis Mediated by RIG-I/MAVS.
  • Rescue of recombinant Newcastle disease virus from cDNA.
  • Competitive detection of influenza neutralizing antibodies using a novel bivalent fluorescence-based microneutralization assay (BiFMA).
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    33 TRIPLES      17 PREDICATES      34 URIs      9 LITERALS

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    1 grants:7707666bba4cb285eb4abaf355ac03de sg:abstract DESCRIPTION (provided by applicant): Arenaviruses include several causative agents of Hemorrhagic Fever (HF) disease in humans that are associated with high morbidity and significant mortality. Moreover, weaponized forms of arenaviruses pose a serious threat as agents of bioterrorism. Public health concerns posed by arenaviruses are aggravated by the lack of licensed vaccines and by current anti-arenavirus therapy limited to the off-label use of ribavirin, which is only partially effective and often associated with severe side effects. Limitations in the study of HF arena-viruses include the manipulation of live forms of these agents under BioSafety Level (BSL) 4 laboratories and the requirement of secondary assays for detection of the virus. Development of valid single-cycle infectious surrogates that allow the study of HF arenavirus under less-strict BSL2 facilities and that express a reporter gene for easy viral detection will facilitate the identification of prophylactic and therapeutic strategies using safe, sensitive and specific screening assays compatible with High Throughput Screening (HTS) technologies. Furthermore, they will also represent promising vaccine approaches that circumvent concerns about potential out-of-control replication of attenuated vaccine strains that might lead to disease. Recently, we have described, for the first time, the generation of a single-cycle infectious, reporter-expressing, Old World Lymphocytic Choriomeningitis Virus (LCMV) where we replaced the viral glycoprotein (GP) with a reporter green fluorescent protein (GFP), rLCMV?GP/GFP. Infectious virus was achieved via genetic trans- complementation with cell lines constitutively expressing LCMV GP. This system allowed us to study multiple aspects of the virus and to develop screening assays for detection and quantification of neutralizing antibodies and identification of viral inhibitors. We were also able to extend our work to Lassa virus (LASV), an HF member of the Old World arenavirus, by generating LASV GP-expressing cell lines and LASV GP-pseudotyped rLCMV?GP/GFP. Since Old World and New World arena-viruses differ in their reservoirs, cellular receptor use for viral entry, and RNA genome composition, the development of valid surrogates to study New World arenavirus is imperative to provide researchers a way to study all aspects of the virus biology, to identify antivirals, and to develop vaccines against New World arenaviruses under less strict biosafety laboratories. In this application we propose to expand our recently described technology to the study of New World arenavirus by generating a single-cycle infectious, reporter-expressing, attenuated vaccine strain Candid#1 (rCan?GP/GFP).
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    29 sg:startYear 2012
    30 sg:title Single-cycle Infectious Candid#1 to Study Hemorrhagic Fever New World Arenavirus
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