<p>Persistence of viral reservoirs prevents a cure or functional cure for HIV. Efforts to eradicate viral reservoirs have been constrained by the difficulties of identifying and eliminating rare, heterogeneous viral reservoir cells in vivo. Single-modality interventions such as “shock and kill” have faced persistent challenges despite decades of effort, highlighting the need for complementary strategies that more precisely target infected cells. In this review, I summarize our 20 years of effort in developing an HIV Rev-dependent lentiviral vector for selective targeting of viral reservoirs. This lentiviral vector expresses therapeutic genes under the control of HIV Tat and Rev, conferring high specificity. In vitro, superinfection of HIV-infected cells with the Rev-dependent particle can lead to the identification and selective killing of infected cells. In vivo, injection of Rev-dependent lentiviral particles into SIV-infected rhesus macaques stimulates antiviral immunity, leading to reduction of viral reservoirs and inhibition of viral rebound. We designate this Rev vector-based therapeutic approach as Rev-dependent HIV Immunotherapy (RHIT). The RHIT approach integrates three complementary reservoir-targeting strategies: (1) RHIT-mediated killing of reservoir cells via Rev-dependent therapeutic gene expression; (2) RHIT-mediated inhibition of active HIV replication via defective interfering particles; and (3) RHIT-induced anti-HIV immunity via induction of neutralizing antibodies and cell-mediated immune responses. In this review, I also discuss limitations and challenges for the future development of RHIT.</p>