Role of IFN-gamma-induced indoleamine 2,3 dioxygenase and inducible nitricoxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells

An in vitro model of human CMV infection of primary retinal pigment epithel ial (RPE) cells was used to study the effects of cytokines on CMV replicati on in these cells, which are targets of CMV infection in vivo. IFN-gamma an d IFN-beta were potent inhibitors of CMV replication in RPE cells, while TN F-alpha, IL-1 beta, or TGF-beta 2 did not affect viral replication. Inhibit ion by IFN-gamma, and to a lesser extent IFN-beta, was almost completely re versed by addition of L-tryptophan to the culture medium, strongly implicat ing the indoleamine 2,3 dioxygenase (IDO) pathway. Polyadenylated IDO mRNA accumulation was detected as early as 2 h after IFN stimulation. Furthermor e, CMV blocked the production of nitric oxide by the inducible form of nitr ic oxide synthase, This inhibition depended on a functional viral genome. H owever, exogenous nitric oxide significantly inhibited viral protein expres sion in RPE cells. Thus, CMV infection blocks the inducible nitric oxide sy nthase pathway activated by IFN-gamma and IL-1 beta, but cannot counteract the IFN-induced IDO pathway, which ultimately controls its replication in p rimary human RPE cells.