title: C-terminal trans-activation sub-region of VP16 is uniquely required for forskolin-induced herpes simplex virus type 1 reactivation from quiescently infected-PC12 cells but not for replication in neuronally differentiated-PC12 cells.
abstract: The HSV-1 tegument protein VP16 contains a trans-activation domain (TAD) that is required for induction of immediate early (IE) genes during lytic infection and induced reactivation from latency. Here we report the differential contributions of the two sub-regions of the TAD in neuronal and non-neuronal cells during activation of IE gene expression, virus replication, and reactivation from quiescently infected (QIF)-PC12 cells. Our studies show that VP16- and chemical (hexamethylenebisacetamide)-induced IE gene activation is attenuated in neuronal cells. Irrespective of neuronal or non-neuronal cell backgrounds, IE gene activation demonstrated a greater requirement for the N-terminal sub-region of VP16 TAD (VP16N) than the C-terminal sub-region (VP16C). In surprising contrast to these findings, a recombinant virus (RP4) containing the VP16N deletion was capable of modest forskolin-induced reactivation whereas a recombinant (RP3) containing a deletion of VP16C was incapable of stress-induced reactivation from QIF-PC12 cells. These unique process-dependent functions of the VP16 TAD sub-regions may be important during particular stages of the virus life cycle (lytic, entrance, and maintenance of a quiescent state and reactivation) when viral DNA would be expected to be differentially modified.
authors.affiliation: Department of Oral Health Practice, Division of Oral Medicine, Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, KY 40536-0297, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Danaher
authors.forename: Ross K
authors.initials: RK
authors.lastname: Cook
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Triezenberg
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Jacob
authors.forename: Craig S
authors.initials: CS
authors.lastname: Miller
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005576:Colforsin / Q000494:pharmacology; D017781:Genes, Immediate-Early; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000821:virology*; D016716:PC12 Cells; D051381:Rats; D015533:Transcriptional Activation; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65; D005576:Colforsin