title: A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18(INK4c) To Promote Reactivation from Latency.
abstract: Gammaherpesviruses (GHVs) carry homologs of cellular genes, including those encoding a viral cyclin that promotes reactivation from latent infection. The viral cyclin has reduced sensitivity to host cyclin-dependent kinase inhibitors in vitro; however, the in vivo significance of this is unclear. Here, we tested the genetic requirement for the viral cyclin in mice that lack the host inhibitors p27(Kip1) and p18(INK4c), two cyclin-dependent kinase inhibitors known to be important in regulating B cell proliferation and differentiation. While the viral cyclin was essential for reactivation in wild-type mice, strikingly, it was dispensable for reactivation in mice lacking p27(Kip1) and p18(INK4c). Further analysis revealed that genetic ablation of only p18(INK4c) alleviated the requirement for the viral cyclin for reactivation from latency. p18(INK4c) regulated reactivation in a dose-dependent manner so that the viral cyclin was dispensable in p18(INK4c) heterozygous mice. Finally, treatment of wild-type cells with the cytokine BAFF, a known attenuator of p18(INK4c) function in B lymphocytes, was also able to bypass the requirement for the viral cyclin in reactivation. These data show that the gammaherpesvirus viral cyclin functions specifically to bypass the cyclin-dependent kinase inhibitor p18(INK4c), revealing an unanticipated specificity between a GHV cyclin and a single cyclin-dependent kinase inhibitor.
  
  
  OBJECTIVE
  The gammaherpesviruses (GHVs) cause lifelong infection and can cause chronic inflammatory diseases and cancer, especially in immunosuppressed individuals. Many GHVs encode a conserved viral cyclin that is required for infection and disease. While a common property of the viral cyclins is that they resist inhibition by normal cellular mechanisms, it remains unclear how important it is that the GHVs resist this inhibition. We used a mouse GHV that either contained or lacked a viral cyclin to test whether the viral cyclin lost importance when these inhibitory pathways were removed. These studies revealed that the viral cyclin was required for optimal function in normal mice but that it was no longer required following removal or reduced function of a single cellular inhibitor. These data define a very specific role for the viral cyclin in bypassing one cellular inhibitor and point to new methods to intervene with viral cyclins.
authors: Immunology and Microbiology Department, University of Colorado Denver School of Medicine, Aurora, Colorado, USA.
authors: Lisa M
authors: LM
authors: Williams
authors: Immunology and Microbiology Department, University of Colorado Denver School of Medicine, Aurora, Colorado, USA.
authors: Brian F
authors: BF
authors: Niemeyer
authors: Biochemistry Department, Tulane University, New Orleans, Louisiana, USA.
authors: David S
authors: DS
authors: Franklin
authors: Anesthesiology Department, University of Colorado Denver School of Medicine, Aurora, Colorado, USA.
authors: Eric T
authors: ET
authors: Clambey
authors: Immunology and Microbiology Department, University of Colorado Denver School of Medicine, Aurora, Colorado, USA linda.vandyk@ucdenver.edu.
authors: Linda F
authors: LF
authors: van Dyk
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000494:pharmacology; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency; D016213:Cyclins / Q000378:metabolism* / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D018142:Gammaherpesvirinae / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014775:Virus Activation / Q000187:drug effects / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*
chemical_list: D053264:B-Cell Activating Factor; C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; D016213:Cyclins; D017931:DNA Primers; C505720:Tnfsf13b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27