title: CD40 ligand exhibits a direct antiviral effect on Herpes Simplex Virus type-1 infection via a PI3K-dependent, autophagy-independent mechanism.
abstract: The interaction between CD40 and its ligand, CD40L/CD154, is crucial for the efficient initiation and regulation of immune responses against viruses. Herpes Simplex Virus type-1 (HSV-1) is a neurotropic virus capable of manipulating host responses and exploiting host proteins to establish productive infection. Herein we have examined the impact of CD40L-mediated CD40 activation on HSV-1 replication in U2OS cells stably expressing the CD40 receptor. Treatment of these cells with CD40L significantly reduced the HSV-1 progeny virus compared to non-treated cells. The activation of CD40 signaling did not affect the binding of HSV-1 virions on the cell surface but rather delayed the translocation of VP16 to the nucleus, affecting all stages of viral life cycle. Using pharmacological inhibitors and RNAi we show that inhibition of PI3 kinase but not autophagy reverses the effects of CD40L on HSV-1 replication. Collectively, these data demonstrate that CD40 activation exerts a direct inhibitory effect on HSV-1, initiating from the very early stages of the infection by exploiting PI3 kinase-dependent but autophagy-independent mechanisms.
authors.affiliation: Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Crete, Greece.
authors.forename: Virginia-Maria
authors.initials: VM
authors.lastname: Vlahava
authors.affiliation: Molecular and Cellular Biology Laboratory, Medical School, University of Crete, Heraklion, Crete, Greece; Institute of Molecular Biology & Biotechnology, FORTH, Heraklion, Crete, Greece.
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.affiliation: Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Crete, Greece. Electronic address: sourvino@med.uoc.gr.
authors.forename: George
authors.initials: G
authors.lastname: Sourvinos
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D001596:Benzylamines / Q000494:pharmacology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000873:Anthracenes; D000998:Antiviral Agents; D000071187:Autophagy-Related Protein 5; D001596:Benzylamines; D023201:CD40 Ligand; D002867:Chromones; D017405:Herpes Simplex Virus Protein Vmw65; D048031:JNK Mitogen-Activated Protein Kinases; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; C502778:ATG5 protein, human; C477012:MAP1LC3A protein, human; C000591235:spautin-1; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C040929:bafilomycin A1
keywords: Atg5; Autophagy; CD40 ligand; HSV-1; PIK3K; VP16