We have recently developed an HIV-1 packaging cell line, psi 422, as an improved tool for anti-HIV gene therapy. After stable transfection with an HIV-1 or HIV-2 vector, psi 422 has been shown to synthesize virions able to transduce CD4+ T cells and macrophages. We now report that HIV vectors per se, in the absence of antiviral genes, inhibit HIV infection of transduced cells. This antiviral effect was shown to be due, at least in part, to a TAR and RRE decoy effect. These data highlight further advantages of HIV-derived gene delivery systems for HIV therapy, in addition to CD4 cell targeting and the ability to transduce nondividing cells.