LIGAND INDUCTION OF RETINOIC ACID RECEPTORS ALTERS AN ACUTE INFECTIONBY MURINE CYTOMEGALOVIRUS

Here we report that administration of retinoids can alter the outcome of an acute murine cytomegalovirus (MCMV) infection. We show that a cr ucial viral control element, the major immediate-early enhancer, can b e activated by retinoic acid (RA) via multiple RA-responsive elements (DR2) that bind retinoid X receptor-retinoic acid receptor (RAR) heter odimers with apparent dissociation constants ranging from 15 to 33 nhl . Viral growth is dramatically increased upon RA treatment of infected tissue culture cells. Using synthetic retinoid receptor-specific agon ists and antagonists, we provide evidence that RAR activation in cells is required for mediating the response of MCMV to RA. Oral administra tion 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, th ese chemical genetic experiments provide evidence that an RAR-mediated pathway can modulate in vitro and in vivo infections by MCMV.