Journal of NeuroVirology

, Volume 16, Issue 5, pp 405–409

Role of a cdk5-associated protein, p35, in herpes simplex virus type 1 replicationin vivo

  • Steve D Haenchen
  • Jeff A Utter
  • Adam M Bayless
  • Rick T Dobrowsky
  • David J Davido
Short communication

Abstract

Previous studies have shown that herpes simplex virus type 1 (HSV-1) replication is inhibited by the cyclin-dependent kinase (cdk) inhibitor roscovitine. One roscovitine-sensitive cdk that functions in neurons is cdk5, which is activated in part by its binding partner, p35. Because HSV establishes latent infections in sensory neurons, we sought to determine the role p35 plays in HSV-1 replicationin vivo. For these studies, wild-type (wt) and p35-/- mice were infected with HSV-1 using the mouse ocular model of HSV latency and reactivation. The current results indicate that p35 is an important determinant of viral replicationin vivo.

Keywords

cdk5 HSV-1 HSV-1 latency and reactivation p35 p35 knockout mice 

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References

  1. Advani SJ, Hagglund R, Weichselbaum RR, Roizman B (2001). Posttranslational processing of infected cell proteins 0 and 4 of herpes simplex virus 1 is sequential and reflects the subcellular compartment in which the proteins localize.J Virol 75: 7904–7912.PubMedCrossRefGoogle Scholar
  2. Balliet JW, Schaffer PA (2006). Point mutations in herpes simplex virus type 1 oriL, but not in oriS, reduce pathogenesis during acute infection of mice and impair reactivation from latency.J Virol 80: 440–450.PubMedCrossRefGoogle Scholar
  3. Chae T, Kwon YT, Bronson R, Dikkes P, Li E, Tsai LH (1997). Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality.Neuron 18: 29–42.PubMedCrossRefGoogle Scholar
  4. Coen DM, Kosz-Vnenchak M, Jacobson JG, Leib DA, Bogard CL, Schaffer PA, Tyler KL, Knipe DM (1989). Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.Proc Natl Acad Sci U S A 86: 4736–4740.PubMedCrossRefGoogle Scholar
  5. Davido DJ, Leib DA, Schaffer PA (2002). The cyclindependent kinase inhibitor roscovitine inhibits the transactivating activity and alters the posttranslational modification of herpes simplex virus type 1 ICP0.J Virol 76: 1077–1088.PubMedCrossRefGoogle Scholar
  6. Fields BN, Knipe DM, Howley PM (2007).Fields Virology, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.Google Scholar
  7. Fu AK, Fu WY, Ng AK, Chien WW, Ng YP, Wang JH, Ip NY (2004). Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity.Proc Natl Acad Sci USA 101: 6728–6733.PubMedCrossRefGoogle Scholar
  8. Gao C, Negash S, Guo HT, Ledee D, Wang HS, Zelenka P (2002). CDK5 regulates cell adhesion and migration in corneal epithelial cells.Mol Cancer Res 1: 12–24.PubMedGoogle Scholar
  9. Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, Blair LA, Marshall J, Mao Z (2003). Cdk5-mediated inhibition of the protective effects of transcription factorMEF2 in neurotoxicity-induced apoptosis.Neuron 38: 33–46.PubMedCrossRefGoogle Scholar
  10. Halford WP, Balliet JW, Gebhardt BM (2004). Re-evaluating natural resistance to herpes simplex virus type 1.J Virol 78: 10086–10095.PubMedCrossRefGoogle Scholar
  11. Halford WP, Schaffer PA (2000). Optimized viral dose and transient immunosuppression enable herpes simplex virus ICP0-null mutants to establish wild-type levels of latency in vivo.J Virol 74: 5957–5967.PubMedCrossRefGoogle Scholar
  12. Ino H, Chiba T (1996). Intracellular localization of cyclindependent kinase 5 (CDK5) in mouse neuron: CDK5 is located in both nucleus and cytoplasm.Brain Res 732: 179–185.PubMedCrossRefGoogle Scholar
  13. Jung HW, Jung CR, Choi BK, Vinay DS, Hill JM, Gebhardt BM, Kwon BS (2004). Herpesvirus infection of ICAM-1-deficient mice.Curr Eye Res 29: 201–208.PubMedCrossRefGoogle Scholar
  14. Katz JP, Bodin ET, Coen DM (1990). Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants.J Virol 64: 4288–4295.PubMedGoogle Scholar
  15. Ko J, Humbert S, Bronson RT, Takahashi S, Kulkarni AB, Li E, Tsai LH (2001). p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment.J Neurosci 21: 6758–6771.PubMedGoogle Scholar
  16. Kosz-Vnenchak M, Coen DM, Knipe DM (1990). Restricted expression of herpes simplex virus lytic genes during establishment of latent infection by thymidine kinasenegative mutant viruses.J Virol 64: 5396–5402.PubMedGoogle Scholar
  17. Lee JH, Kim HS, Lee SJ, Kim KT (2007). Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death.J Cell Sci 120: 2259–2271.PubMedCrossRefGoogle Scholar
  18. Leib DA, Coen DM, Bogard CL, Hicks KA, Yager DR, Knipe DM, Tyler KL, Schaffer PA (1989). Immediateearly regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency.J Virol 63: 759–768.PubMedGoogle Scholar
  19. Lew J, Huang QQ, Qi Z, Winkfein RJ, Aebersold R, Hunt T, Wang JH (1994). A brain-specific activator of cyclindependent kinase 5.Nature 371: 423–426.PubMedCrossRefGoogle Scholar
  20. Link MA, Schaffer PA (2007). Herpes simplex virus type 1 C-terminal variants of the origin binding protein (OBP), OBPC-1 and OBPC-2, cooperatively regulate viral DNA levels in vitro, and OBPC-2 affects mortality in mice.J Virol 81: 10699–10711.PubMedCrossRefGoogle Scholar
  21. Malumbres M, Barbacid M (2009). Cell cycle, CDKs and cancer: a changing paradigm.Nat Rev Cancer 9: 153–166.PubMedCrossRefGoogle Scholar
  22. National Research Council (1996).Guide for the care and use of laboratory animals. Washington, DC: National Academy Press.Google Scholar
  23. Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH (1998). The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity.Nature 395: 194–198.PubMedCrossRefGoogle Scholar
  24. Nikolic M, Dudek H, Kwon YT, Ramos YF, Tsai LH (1996). The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation.Genes Dev 10: 816–825.PubMedCrossRefGoogle Scholar
  25. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996). Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death.Proc Natl Acad Sci U S A 93: 11173–11178.PubMedCrossRefGoogle Scholar
  26. Qu D, Li Q, Lim HY, Cheung NS, Li R, Wang JH, Qi RZ (2002). The protein SET binds the neuronal Cdk5 activator p35nck5a and modulates Cdk5/p35nck5a activity.J Biol Chem 277: 7324–7332.PubMedCrossRefGoogle Scholar
  27. Rosales JL, Lee KY (2006). Extraneuronal roles of cyclindependent kinase 5.Bioessays 28: 1023–1034.PubMedCrossRefGoogle Scholar
  28. Sawtell NM, Thompson RL, Haas RL (2006). Herpes simplex virus DNA synthesis is not a decisive regulatory event in the initiation of lytic viral protein expression in neurons in vivo during primary infection or reactivation from latency.J Virol 80: 38–50.PubMedCrossRefGoogle Scholar
  29. Schaffer PA, Aron GM, Biswal N, Benyesh-Melnick M (1973). Temperature-sensitive mutants of herpes simplex virus type 1: isolation, complementation and partial characterization.Virology 52: 57–71.PubMedCrossRefGoogle Scholar
  30. Schang LM, Bantly A, Schaffer PA (2002). Explantinduced reactivation of herpes simplex virus occurs in neurons expressing nuclear cdk2 and cdk4.J Virol 76: 7724–7735.PubMedCrossRefGoogle Scholar
  31. Schang LM, Phillips J, Schaffer PA (1998). Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription.J Virol 72: 5626–5637.PubMedGoogle Scholar
  32. Schang LM, Rosenberg A, Schaffer PA (1999). Transcription of herpes simplex virus immediate-early and early genes is inhibited by roscovitine, an inhibitor specific for cellular cyclin-dependent kinases.J Virol 73: 2161–2172.PubMedGoogle Scholar
  33. Schang LM, Rosenberg A, Schaffer PA (2000). Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins.J Virol 74: 2107–2120.PubMedCrossRefGoogle Scholar
  34. Smith DS, Tsai LH (2002). Cdk5 behind the wheel: a role in trafficking and transport?Trends Cell Biol 12: 28–36.PubMedCrossRefGoogle Scholar
  35. Strand SS, Leib DA (2004). Role of the VP16-binding domain of vhs in viral growth, host shutoff activity, and pathogenesis.J Virol 78: 13562–13572.PubMedCrossRefGoogle Scholar
  36. Strelow LI, Leib DA (1995). Role of the virion host shutoff (vhs) of herpes simplex virus type 1 in latency and pathogenesis.J Virol 69: 6779–6786.PubMedGoogle Scholar
  37. Tang D, Wang JH (1996). Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators.Prog Cell Cycle Res 2: 205–216.PubMedCrossRefGoogle Scholar
  38. Thompson RL, Preston CM, Sawtell NM (2009). De novo synthesis of VP16 coordinates the exit from HSV latency in vivo.PLoS Pathog 5: e1000352.PubMedCrossRefGoogle Scholar
  39. Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994). p35 is a neural-specific regulatory subunit of cyclindependent kinase 5.Nature 371: 419–423.PubMedCrossRefGoogle Scholar
  40. Zhang J, Li H, Herrup K (2010). Cdk5 nuclear localization is p27-dependent in nerve cells: implications for cell cycle suppression and caspase-3 activation.J Biol Chem 285: 14052–14061.PubMedCrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2010

Authors and Affiliations

  • Steve D Haenchen
    • 1
  • Jeff A Utter
    • 1
  • Adam M Bayless
    • 1
  • Rick T Dobrowsky
    • 2
  • David J Davido
    • 1
  1. 1.Department of Molecular BiosciencesUniversity of KansasLawrenceUSA
  2. 2.Department of Pharmacology and ToxicologyUniversity of Kansas School of PharmacyLawrenceUSA

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