HIV-1　Tat　is　one　of　six　regulatory　Proteins　that　are　required　for　viral　replication　and　is　an　attractive　target　for　the　development　of　new　anti-HIV　agents.　The　induction　of　oxidative　stress,　as　shown　with　Tat,　may　have　a　bearing　on　the　transactivation　mechanism　of　transcription.　The　transcription　factor　Nrf2　is　a　key　player　in　the　regulation　of　genes　encoding　many　antioxidative　response　enzymes.　Thus,　the　effect　of　Nrf2　oil　Tat-induced　HIV-1　transcription　was　Studied　in　MAGI　cells.　We　found,　for　the　first　time,　that　Tat　enhanced　cellular　expression　of　Nrf2　at　the　transcriptional　and　protein　levels　in　these　cells,　and　Tat　activated　antioxidant　response　element-driven　gene　expression.　Tat　simultaneously　decreased　the　intracellular　glutathione　(GSH)　levels　and　increased　reactive　oxygen　species　(ROS)　production.　The　coordinated　induction　of　ROS　production,　GSH　depletion,　and　nuclear　Nrf2　accumulation　induced　by　Tat　Suggests　that　NFf2　activation　induced　by　Tat　is　not　Sufficient　for　protection　against　Tat-induced　oxidative　stress.　Furthermore,　when　cells　were　pretreated　with　scavengers　of　hydrogen　peroxide　such　as　N-acetylcysteine,　or　overexpression　of　Nrf2,　OF　Keap1　knockdown　by　siRNA,　Tat-indUced　HIV-1　LTR　transactivation　was　Suppressed,　whereas　buthionine　sulfoximine　or　NFf2　knockdown　by　siRNA　potentiated　Tat-induced　HIV-1　INK　transactivation.　Similar　results　were　found　in　HIV-IIIB　Virus　infection.　Taken　together,　these　data　clearly　show　that　Nrf2　inhibits　Tat-induced　HIV-1　LTR　transactivation.　This　negative　regulation　of　Tat-induced　HIV-1　LTR　transactivation　by　Nrf2　might　be　all　important　mechanism　leading　to　its　anti-HIV-1　replicative　activity.　(C)　2009　Elsevier　Inc.　All　rights　reserved.