title: Inhibition of herpes simplex virus type 1 replication by adeno-associated virus rep proteins depends on their combined DNA-binding and ATPase/helicase activities.
abstract: Adeno-associated virus (AAV) has previously been shown to inhibit the replication of its helper virus herpes simplex virus type 1 (HSV-1), and the inhibitory activity has been attributed to the expression of the AAV Rep proteins. In the present study, we assessed the Rep activities required for inhibition of HSV-1 replication using a panel of wild-type and mutant Rep proteins lacking defined domains and activities. We found that the inhibition of HSV-1 replication required Rep DNA-binding and ATPase/helicase activities but not endonuclease activity. The Rep activities required for inhibition of HSV-1 replication precisely coincided with the activities that were responsible for induction of cellular DNA damage and apoptosis, suggesting that these three processes are closely linked. Notably, the presence of Rep induced the hyperphosphorylation of a DNA damage marker, replication protein A (RPA), which has been reported not to be normally hyperphosphorylated during HSV-1 infection and to be sequestered away from HSV-1 replication compartments during infection. Finally, we demonstrate that the execution of apoptosis is not required for inhibition of HSV-1 replication and that the hyperphosphorylation of RPA per se is not inhibitory for HSV-1 replication, suggesting that these two processes are not directly responsible for the inhibition of HSV-1 replication by Rep.
authors.affiliation: Institute of Virology, University of Zurich, Winterthurerstrasse 266a, CH-8057 Zurich, Switzerland.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Glauser
authors.forename: Michael
authors.initials: M
authors.lastname: Seyffert
authors.forename: Regina
authors.initials: R
authors.lastname: Strasser
authors.forename: Marco
authors.initials: M
authors.lastname: Franchini
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Laimbacher
authors.forename: Christiane
authors.initials: C
authors.lastname: Dresch
authors.forename: Anna Paula
authors.initials: AP
authors.lastname: de Oliveira
authors.forename: Rebecca
authors.initials: R
authors.lastname: Vogel
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
authors.forename: Anna
authors.initials: A
authors.lastname: Salvetti
authors.forename: Mathias
authors.initials: M
authors.lastname: Ackermann
authors.forename: Cornel
authors.initials: C
authors.lastname: Fraefel
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002522:Chlorocebus aethiops; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism; D000229:Dependovirus / Q000254:growth & development / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000502:physiology*; D010766:Phosphorylation; D017384:Sequence Deletion; D015534:Trans-Activators / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D015534:Trans-Activators; D014764:Viral Proteins; C045264:replication initiator protein; D000251:Adenosine Triphosphatases; D004265:DNA Helicases