Ligand induction of retinoic acid receptors alters an acute infection by murine cytomegalovirus.
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.
Angulo
A
A
Departments of Immunology and Molecular Biology, Division of Virology, The Scripps Research Institute, La Jolla, California 92037, USA.
Chandraratna
R A
RA
LeBlanc
J F
JF
Ghazal
P
P
D016475:3T3 Cells; D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D005260:Female; D006566:Herpesviridae Infections / Q000503:physiopathology* / Q000821:virology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012176:Retinoids / Q000494:pharmacology; D014212:Tretinoin / Q000008:administration & dosage*; D014779:Virus Replication / Q000187:drug effects*
D001565:Benzoates; D008024:Ligands; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; C096920:AGN 193109