: Lymphocytic choriomeningitis virus (LCMV) provides one of the most valuable model systems in the field of viral pathogenesis. Studies with LCMV will improve our understanding of clinically important human pathogens, including Lassa fever virus and other emerging arenaviruses that pose a real threat to human health. A newly developed reverse genetic system allows now to conduct a detailed characterization of the cis-acting signals and trans-acting factors involved in virus RNA synthesis, control of gene expression, maturation and budding. This system also provides the foundations to rescue infectious LCMV entirely from plasmids. The ability to generate predetermined mutations within the LCMV genome will contribute to the elucidation of the molecular mechanisms underlying virus-host interactions, including viral persistence and associated disease, which are the long-term goals of the proposed studies with the following specific aims: 1)Characterization of cis-acting signals involved in the regulation of LCMV will identify and molecularly dissect the viral promoters. Likewise, mutational studies will determine the role of the panhandle structure and intergenic regions in virus RNA synthesis. 2) Investigation of the molecular bases of the Z-mediated inhibition of LCMV minigenome expression. The sequence and structural requirements of Z to exert its inhibitory activity will be determined. Studies will be done to elucidate the interactions of Z with virus RNA, as well as L and NP proteins that contribute to Z's inhibitory activity. 3) Production of infectious LCMV from DNA. Cis-and trans-acting requirements and optimal experimental conditions for packaging and budding of LCMV minigenomes will be defined. Plasmid derived S and L genomic RNAs containing genetic tags will be constructed and intracellularly coexrpessed with the viral trans-acting proteins required to initiate a productive infectious cycle, thus resulting in the rescue of infectious LCMV. This will provide a new and powerful approach to the study of the arenavirus molecular biology and pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology Study Section (VR)
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Repik, Patricia M
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Scripps Research Institute
La Jolla
United States
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Iwasaki, Masaharu; de la Torre, Juan C (2018) A Highly Conserved Leucine in Mammarenavirus Matrix Z Protein Is Required for Z Interaction with the Virus L Polymerase and Z Stability in Cells Harboring an Active Viral Ribonucleoprotein. J Virol 92:
Cheng, Benson Y H; Nogales, Aitor; de la Torre, Juan Carlos et al. (2017) Development of live-attenuated arenavirus vaccines based on codon deoptimization of the viral glycoprotein. Virology 501:35-46
Iwasaki, Masaharu; Ng, Cherie T; Cubitt, Beatrice et al. (2016) Residues K465 and G467 within the Cytoplasmic Domain of GP2 Play a Critical Role in the Persistence of Lymphocytic Choriomeningitis Virus in Mice. J Virol 90:10102-10112
Iwasaki, Masaharu; Cubitt, Beatrice; Sullivan, Brian M et al. (2016) The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses. J Virol 90:3187-97
Martínez-Sobrido, Luis; de la Torre, Juan Carlos (2016) Reporter-Expressing, Replicating-Competent Recombinant Arenaviruses. Viruses 8:
Martinez-Sobrido, Luis; de la Torre, Juan Carlos (2016) Novel strategies for development of hemorrhagic fever arenavirus live-attenuated vaccines. Expert Rev Vaccines 15:1113-21
Cunningham, Cameron R; Champhekar, Ameya; Tullius, Michael V et al. (2016) Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence. PLoS Pathog 12:e1005356
Martínez-Sobrido, Luis; Cheng, Benson Yee Hin; de la Torre, Juan Carlos (2016) Reverse Genetics Approaches to Control Arenavirus. Methods Mol Biol 1403:313-51
Ngo, Nhi; Henthorn, Kristina Schimmelpfeng; Cisneros, Maria Isabel et al. (2015) Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication. J Virol 89:10924-33
Cheng, Benson Yee Hin; Ortiz-Riaño, Emilio; de la Torre, Juan Carlos et al. (2015) Arenavirus Genome Rearrangement for the Development of Live Attenuated Vaccines. J Virol 89:7373-84

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