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J Virol, June 1998, p. 4589-4600, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Ligand Induction of Retinoic Acid Receptors Alters an Acute Infection by Murine Cytomegalovirusdagger

Ana Angulo,1 Roshantha A. S. Chandraratna,2 James F. LeBlanc,1 and Peter Ghazal1,*

Departments of Immunology and Molecular Biology, Division of Virology, The Scripps Research Institute, La Jolla, California 92037,1 and Retinoid Research, Allergan Inc., Irvine, California 927132

Received 8 December 1997/Accepted 12 February 1998

Here we report that administration of retinoids can alter the outcome of an acute murine cytomegalovirus (MCMV) infection. We show that a crucial viral control element, the major immediate-early enhancer, can be activated by retinoic acid (RA) via multiple RA-responsive elements (DR2) that bind retinoid X receptor-retinoic acid receptor (RAR) heterodimers with apparent dissociation constants ranging from 15 to 33 nM. Viral growth is dramatically increased upon RA treatment of infected tissue culture cells. Using synthetic retinoid receptor-specific agonists and antagonists, we provide evidence that RAR activation in cells is required for mediating the response of MCMV to RA. Oral administration of RA to infected immunocompetent mice selectively exacerbates an infection by MCMV, while cotreatment with an RAR antagonist protects against the adverse effects of RA on MCMV infection. In conclusion, these chemical genetic experiments provide evidence that an RAR-mediated pathway can modulate in vitro and in vivo infections by MCMV.

* Corresponding author. Mailing address: Departments of Immunology and Molecular Biology, Division of Virology R307B, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 784-8678. Fax (619) 784-8805. E-mail: ghazal{at}scripps.edu.

dagger Publication no. 10753-IMM of The Scripps Research Institute.

J Virol, June 1998, p. 4589-4600, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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