HIV-1 associated neurological dysfunction is a common complication of late stage of HIV-1 infection, and is believed to be due to indirect neuronal injury by infiltration of infected macrophages. Currently, although the highly active antiretroviral regimen can inhibit viral replication and decrease the incidence of the disease, as a therapy, it does not eliminate the viral reservoir that persists in the brain. As such, despite the decreased incidence of the disease since the introduction of HARRT, with the greater life expectancy of infected people, the prevalence of the disease became a prominent clinical problem. The objectives of this proposal are to develop a novel therapeutic approach to target and eliminate infected macrophages in the brain. The specific aims of the proposal are to test the feasibility of this system in targeting infected macrophages. The experiment methods for these specific aims are to achieve HIV-1 Tat- and Rev-dependent expression of a cytolytic gene, anthralysin O from the bacteria Bacillus anthracis, in HIV-1 infected macrophages for cell killing. It is expected that results from the proposed research will promote the development of novel therapeutic strategies to eliminate viral reservoir in the brain. Additionally, the development of HIV-1 - dependent expression of therapeutic and reporter genes in the neuronal system will facilitate the study of viral pathogenesis by providing a novel tool to track viral infection in the brain.