title: Inhibition of mTORC1 inhibits lytic replication of Epstein-Barr virus in a cell-type specific manner.
abstract: BACKGROUND
  Epstein-Barr virus is a human herpesvirus that infects a majority of the human population. Primary infection of Epstein-Barr virus (EBV) causes the syndrome infectious mononucleosis. This virus is also associated with several cancers, including Burkitt's lymphoma, post-transplant lymphoproliferative disorder and nasopharyngeal carcinoma. As all herpesvirus family members, EBV initially replicates lytically to produce abundant virus particles, then enters a latent state to remain within the host indefinitely.
  
  
  METHODS
  Through a genetic screen in Drosophila, we determined that reduction of Drosophila Tor activity altered EBV immediate-early protein function. To further investigate this finding, we inhibited mTOR in EBV-positive cells and investigated subsequent changes to lytic replication via Western blotting, flow cytometry, and quantitative PCR. The student T-test was used to evaluate significance.
  
  
  RESULTS
  mTOR, the human homolog of Drosophila Tor, is an important protein at the center of a major signaling pathway that controls many aspects of cell biology. As the EBV immediate-early genes are responsible for EBV lytic replication, we examined the effect of inhibition of mTORC1 on EBV lytic replication in human EBV-positive cell lines. We determined that treatment of cells with rapamycin, which is an inhibitor of mTORC1 activity, led to a reduction in the ability of B cell lines to undergo lytic replication. In contrast, EBV-positive epithelial cell lines underwent higher levels of lytic replication when treated with rapamycin.
  
  
  CONCLUSIONS
  Overall, the responses of EBV-positive cell lines vary when treated with mTOR inhibitors, and this may be important when considering such inhibitors as anti-cancer therapeutic agents.
authors.affiliation: Department of Biology, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, USA. aladamso@uncg.edu.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Adamson
authors.forename: Brandi T
authors.initials: BT
authors.lastname: Le
authors.forename: Brian D
authors.initials: BD
authors.lastname: Siedenburg
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology / Q000821:virology; D015153:Blotting, Western; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology / Q000821:virology; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus