RETINOID ACTIVATION OF RETINOIC ACID RECEPTORS BUT NOT OF RETINOID-X RECEPTORS PROMOTES CELLULAR-DIFFERENTIATION AND REPLICATION OF HUMAN CYTOMEGALOVIRUS IN EMBRYONAL CELLS

The susceptibility of human embryonal cell line NT-2/D1 to replicate h uman cytomegalovirus (hCMV) is dependent on retinoic acid (RA) stimula tion. Physiological responses to retinoic acid involve two distinct su bfamilies of nuclear receptors, the RA receptors (RARs) and retinoid X receptors (RXRs), which function by activating transcription as heter odimeric or RXR homodimeric complexes from cis-acting DNA response ele ments. At present, it is not clear whether the association between the se two classes of receptors can lead to multiple distinct induction pa thways by signalling one or both receptor partners. Here we have deter mined, by selectively activating endogenous receptors with novel synth etic ligands specific for either RARs or RXRs, what ligand interaction is physiological in the retinoid receptor pathways necessary for indu cing replication of hCMV in differentiated embryonal cells. We show th at ligand binding to RAR alone is sufficient and that exclusive ligand activation of RXR is insufficient for inducing replication of hCMV. W e also find that differentiation and inhibition of NT-2/D1 cell growth are promoted by compounds that signal the RAR pathway. These results provide direct evidence that RAR ligand-mediated physiological respons es are separable and distinct from RXR ligand activation functions. Mo reover, our results provide insight into a hormone response pathway fo r cellular differentiation that might be coopted by hCMV in the host.