The synthetic immunomodulator murabutide has been found to suppress human immunodeficiency virus type-1 (HIV-1) replication, in macrophages, through a regulated expression of cellular factors needed at different steps in the virus replication cycle. To identify cellular genes implicated in the murabutide-induced virus inhibition, we have carried out a differential display analysis on HIV-1-infected macrophages that were treated, or not, with murabutide. Sequencing of the differentially regulated cDNA bands and verification of the reproducibility of the murabutide effects, by reverse transcription-polymerase chain reaction or by Northern blotting, revealed an up-regulated expression of 21 genes and a down-regulation of seven others. The murabutide-regulated genes encoded proteins implicated in DNA binding, regulation of transcription, oxidative stress, metal binding, and other physiological functions. Six of the genes corresponded to unassigned/expressed sequence tags with yet unknown function. Among the genes which were up-regulated by murabutide and with established effects on inhibiting virus transcription, was the octamer binding factor 1 (Oct-1). We demonstrate the ability of murabutide to induce enhanced Oct-1 protein expression and DNA-binding activity in macrophages. Furthermore, our findings suggest the potential implication of additional transcription factors and metal-binding proteins in mediating the inhibitory effect of murabutide on virus transcription.