title: Oligoadenylate synthetase/protein kinase R pathways and alphabeta TCR+ T cells are required for adenovirus vector: IFN-gamma inhibition of herpes simplex virus-1 in cornea.
abstract: An adenoviral (Ad) vector containing the murine IFN-gamma transgene (Ad:IFN-gamma) was evaluated for its capacity to inhibit HSV-1. To measure effectiveness, viral titers were analyzed in cornea and trigeminal ganglia (TG) during acute ocular HSV-1 infection. Ad:IFN-gamma potently suppressed HSV-1 replication in a dose-dependent fashion, requiring IFN-gamma receptor. Moreover, Ad:IFN-gamma was effective when delivered -72 and -24 h before infection as well as 24 h postinfection. Associated with antiviral opposition, TG from Ad:IFN-gamma-transduced mice harbored fewer T cells. Also related to T cell involvement, Ad:IFN-gamma was effective but attenuated in TG from alphabeta TCR-deficient mice. In corneas, alphabeta TCR(+) T cells were obligatory for protection against viral multiplication. Type I IFN involvement amid antiviral efficacy of Ad:IFN-gamma was further investigated because types I and II IFN pathways have synergistic anti-HSV-1 activity. Ad:IFN-gamma inhibited viral reproduction in corneas and TG from alphabeta IFNR-deficient (CD118(-/-)) mice, although viral titers were 2- to 3-fold higher in cornea and TG compared with wild-type mice. The absence of IFN-stimulated antiviral proteins, 2'-5' oligoadenylate synthetase/RNase L, and dsRNA-dependent protein kinase R completely eliminated the antiviral effectiveness of Ad:IFN-gamma. Collectively, the results demonstrate the following: 1) nonexistence of type I IFN receptor does not abolish defense of Ad:IFN-gamma against HSV-1; 2) antiviral pathways oligoadenylate synthetase-RNase L and protein kinase R are mandatory; and 3) alphabeta TCR(+) T cells are compulsory for Ad:IFN-gamma effectiveness against HSV-1 in cornea but not in TG.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Bobbie Ann
authors.initials: BA
authors.lastname: Austin
authors.forename: William P
authors.initials: WP
authors.lastname: Halford
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.forename: Daniel J J
authors.initials: DJ
authors.lastname: Carr
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000502:physiology*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003315:Cornea / Q000821:virology*; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000502:physiology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology*; D017471:Receptors, Interferon / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D012668:Trigeminal Ganglion / Q000821:virology; D019892:eIF-2 Kinase / Q000502:physiology*; D000096743:Interferon gamma Receptor
chemical_list: D015088:2',5'-Oligoadenylate Synthetase; D007371:Interferon-gamma; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017471:Receptors, Interferon; D019892:eIF-2 Kinase; D000096743:Interferon gamma Receptor