Infection by the human immunodeficiency virus (HIV) has remained refractory to treatment, and molecular genetic interventions have been developed for the treatment of the acquired immunodeficiency syndrome (AIDS). Previous studies have focused on the development of gene products which inhibit productive HIV replication, including transdominant proteins, RNA decoys and ribozymes. In this report, we show that appropriate expression vectors which optimize production and regulated synthesis of a transdominant mutant form of Rev improve its antiviral effect. The combination of a strong constitutive enhancer, a Tat activation response (TAR) regulatory element and transdominant Rev take advantage of three aspects of early viral gene expression to confer increased resistance to HIV replication. This vector may be useful, alone or in combination with other antiviral genes, to provide gene therapy for AIDS.