The feasibility of using a trans-dominant interfering human immunodeficiency virus type 1 (HIV-1) envelope mutant for inducible gene therapy of HIV infection was investigated. Genes encoding wild-type or mutant glycoproteins were introduced into CD4+ cells, where they were stably maintained but not expressed until induced. Envelope (env) gene expression was dependent upon the viral regulatory protein Tat. Induction of the mutant env resulted in resistance to cytopathic effects mediated by wild-type envelope and decreased infectious vector virus production. When cells containing the mutant env gene were infected with wild-type virus, viral spread was inhibited. The fact that maintenance of the env gene was stable over time suggests that inducible gene therapy using the dominantly interfering env mutant may be a feasible approach to slowing the progression of HIV-1 disease. The expression of defective viral genes by cells is a possible strategy for abrogating human immunodeficiency virus (HIV) replication in infected people. A complication of this approach is that continuous expression of such genes is potentially deleterious to cells that are not infected. We describe the restriction of HIV replication by expression of a defective viral gene harbored by the cell. However, the gene is not expressed until the cell is infected by virus.