A critical step in mRNA translation involves the recruitment of the 40S ribosome subunit to the 5'end of capped transcripts. Typically, an ensemble of multi-subunit translation initiation factors executes this task. Viruses provide attractive model systems to study this fundamental process, as they are obligate intracellular parasites, completely dependent upon the protein synthesis machinery resident in their hosts. As mRNA translation is necessary for their replication, viruses are proficient in manipulating not only the host cell translational machinery, but also effectively commandeer the cellular signaling pathways that regulate protein synthesis. This investigation concentrates on Herpes simplex virus-1 (HSV-1), a neurotrophic herpesvirus whose productive replication is responsible for a spectrum of human diseases ranging from self- limiting epithelial sores, severe ocular disease and life threatening encephalitis in immunocompetent hosts to disseminated disease in neonates and immunocompromised individuals. Our long - term objective is to understand how HSV-1 successfully engages and controls the cellular protein synthesis apparatus by both altering and remodeling translation initiation factor complexes required for the production of both cellular and viral polypeptides. As this process is of vital importance for reactivation from latency and vegetative viral growth, our analysis is likely to uncover new targets for potential therapeutic intervention. We specifically propose to i) understand the mechanism(s) whereby cellular translation factor complexes are altered as a result of HSV-1 infection;ii) investigate how the cellular translation repressor 4E- binding protein-1 is controlled in HSV-1 infected cells;and iii) determine how HSV-1 manipulates the cellular kinase mTOR to properly control viral protein synthesis. PUBLIC HEALTH REVELANCE: Like all viruses, herpes simplex virus-1 is completely dependent upon the machinery that produces proteins within its cellular host. By understanding how the virus captures and gains control of the cellular machinery, we hope to come up with new ways of interfering with virus growth. This is important because herpes simplex virus causes a spectrum of human diseases ranging from simple skin sores, to severe eye disease and life threatening brain infections in people with normal immune systems;in addition, the infections are particularly severe in newborns and individuals whose immune systems are not working properly.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Virology - A Study Section (VIRA)
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Challberg, Mark D
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New York University
Schools of Medicine
New York
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Walsh, Derek; Mohr, Ian (2014) Coupling 40S ribosome recruitment to modification of a cap-binding initiation factor by eIF3 subunit e. Genes Dev 28:835-40
Karttunen, Heidi; Savas, Jeffrey N; McKinney, Caleb et al. (2014) Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth. Mol Cell 55:111-22
Kim, Ju Youn; Shiflett, Lora A; Linderman, Jessica A et al. (2014) Using homogeneous primary neuron cultures to study fundamental aspects of HSV-1 latency and reactivation. Methods Mol Biol 1144:167-79
McKinney, Caleb; Zavadil, Jiri; Bianco, Christopher et al. (2014) Global reprogramming of the cellular translational landscape facilitates cytomegalovirus replication. Cell Rep 6:9-17
McKinney, Caleb; Yu, Dong; Mohr, Ian (2013) A new role for the cellular PABP repressor Paip2 as an innate restriction factor capable of limiting productive cytomegalovirus replication. Genes Dev 27:1809-20
Naghavi, Mojgan H; Gundersen, Gregg G; Walsh, Derek (2013) Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread. Proc Natl Acad Sci U S A 110:18268-73
Kim, Ju Youn; Mandarino, Angelo; Chao, Moses V et al. (2012) Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons. PLoS Pathog 8:e1002540
Herdy, Barbara; Jaramillo, Maritza; Svitkin, Yuri V et al. (2012) Translational control of the activation of transcription factor NF-*B and production of type I interferon by phosphorylation of the translation factor eIF4E. Nat Immunol 13:543-50
McKinney, Caleb; Perez, Cesar; Mohr, Ian (2012) Poly(A) binding protein abundance regulates eukaryotic translation initiation factor 4F assembly in human cytomegalovirus-infected cells. Proc Natl Acad Sci U S A 109:5627-32
Kobayashi, Mariko; Kim, Ju-Youn; Camarena, Vladimir et al. (2012) A primary neuron culture system for the study of herpes simplex virus latency and reactivation. J Vis Exp :

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