Brain, Behavior, and Immunity xxx (2004) xxx–xxx www.elsevier.com/locate/ybrbi 0889-1591/$ - see front matter  2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbi.2004.09.001 U NCORR E CTE D PROOF YBRBI 855 No. of Pages 13, DTD=5.0.1 ARTICLE IN PRESS 30 September 2004 Disk Used Vimala (CE) / Hemavathy (TE) Normal Cousins Lecture Stress-associated changes in the steady-state expression of latent Epstein–Barr virus: implications for chronic fatigue syndrome and cancer Ronald Glaser a,b,c,¤ , David A. Padgett a,b,c,d , Monica L. Litsky b , Robert A. Baiocchi c,e , Eric V. Yang a,b , Min Chen b , Peir-En Yeh b , Nancy G. Klimas f , Gailen D. Marshall g , Theresa Whiteside h,i , Ronald Herberman h , Janice Kiecolt-Glaser j , Marshall V. Williams a,c a Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, 333 W. 10th Avenue, Columbus, OH 43210, United States b Institute for Behavioral Medicine Research, The Ohio State University, 333 W. 10th Avenue, Columbus, OH 43210, United States c Comprehensive Cancer Center, The Ohio State University, 300 W. 10th Avenue, Columbus, OH 43210, United States d Department of Oral Biology, The Ohio State University, 305 W. 12th Avenue, Columbus, OH 43210, United States e Department of Internal Medicine, The Ohio State University Medical Center, 1654 Upham Drive, Columbus, OH 43210, United States f Department of Medicine, The University of Miami School of Medicine and VA Medical Center, 1201 NW 16th Street, Miami, FL 33125, United States g Department of Medicine, The University of Mississippi Medical Center, 2500 North State Street, MS 39216-4505, United States h Departments of Pathology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States i University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, United States j Department of Psychiatry, The Ohio State University, 1581 Dodd Drive, Columbus, OH 43210, United States Received 30 August 2004; accepted 1 September 2004 Dedicated to the memory of George F. Solomon. Abstract Antibodies to several Epstein–Barr virus (EBV)-encoded enzymes are observed in patients with diVerent EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown. In this series of studies, we found that puriWed EBV deoxyuridine triphosphate nucleotidohy- drolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-, IL-1, IL-6, IL-8, and IL-10. It also enhanced the ability of natural killer cells to lyse target cells. The EBV dUTPase also signiWcantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN- by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein. It also produced sickness behaviors known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity. The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with chronic fatigue syndrome (CFS) separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inXammation and cancer.  2004 Elsevier Inc. All rights reserved. Keywords: EBV; Viral latency; Chronic fatigue syndrome; Cancer; dUTPase; Stress; Immune dysregulation * Corresponding author. Fax: +1 614 292 1011. E-mail address: glaser.1@osu.edu (R. Glaser). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59