HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Austin, B. A. Articles by Carr, D. J. J. Search for Related Content PubMed PubMed Citation Articles by Austin, B. A. Articles by Carr, D. J. J.

Oligoadenylate Synthetase/Protein Kinase R Pathways and TCR⁺ T Cells Are Required for Adenovirus Vector: IFN- Inhibition of Herpes Simplex Virus-1 in Cornea¹

Bobbie Ann Austin^2,*, William P. Halford, Bryan R. G. Williams and Daniel J. J. Carr^3,*,

^* Department of Ophthalmology and Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Montana State University, Bozeman, MT 59718; and Monash Institute of Medical Research, Monash Medical Center, Clayton, Victoria, Australia

An adenoviral (Ad) vector containing the murine IFN- transgene (Ad:IFN-) 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- potently suppressed HSV-1 replication in a dose-dependent fashion, requiring IFN- receptor. Moreover, Ad:IFN- was effective when delivered –72 and –24 h before infection as well as 24 h postinfection. Associated with antiviral opposition, TG from Ad:IFN--transduced mice harbored fewer T cells. Also related to T cell involvement, Ad:IFN- was effective but attenuated in TG from TCR-deficient mice. In corneas, TCR⁺ T cells were obligatory for protection against viral multiplication. Type I IFN involvement amid antiviral efficacy of Ad:IFN- was further investigated because types I and II IFN pathways have synergistic anti-HSV-1 activity. Ad:IFN- inhibited viral reproduction in corneas and TG from 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-. Collectively, the results demonstrate the following: 1) nonexistence of type I IFN receptor does not abolish defense of Ad:IFN- against HSV-1; 2) antiviral pathways oligoadenylate synthetase-RNase L and protein kinase R are mandatory; and 3) TCR⁺ T cells are compulsory for Ad:IFN- effectiveness against HSV-1 in cornea but not in TG.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Research to Prevent Blindness Stein Research Professorship (to D.J.J.C.) and by Grant AI053108 (to D.J.J.C.) and Core Grant EY12190 from the National Institutes of Health.

² Current address: Laboratory of Immunology, National Institutes of Health, National Eye Institute, 10 Center Drive, Building 10, Room 10N112, Bethesda, MD 20982-1857.

³ Address correspondence and reprint requests to Dr. Daniel J. J. Carr, Department of Microbiology and Immunology, Room 415, Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Boulevard, Oklahoma City, OK 73104. E-mail address: dan-carr{at}ouhsc.edu

⁴ Abbreviations used in this paper: PKR, protein kinase R; OAS, oligoadenylate synthetase; Ad, adenoviral; TG, trigeminal ganglia; RL, RNase L; WT, wild type; p.i., postinfection; TU, transducing unit; DTH, delayed-type hypersensitivity.