Transcription　of　human　immunodeficiency　virus　(HIV-1)　is　activated　by　viral　Tat　protein　which　regulates　HIV-long　terminal　repeat　(LTR)　transcription　and　elongation.　HIV-1　Tat　protein　is　a　substrate　for　the　deacetylase　activity　of　sirtuin　1　(SIRT1).　Here　we　investigate　the　signaling　pathway　involved　in　Tat-induced　HIV-1　transactivation　through　SIRT1.　Western　blot　analysis　showed　a　significant　reduction　in　AMPK　activation　and　downstream　acetyl-CoA　carboxylase　(ACC)　activation　in　response　to　Tat　treatment.　NAD(+)　levels　and　SIRT1　activity　were　also　decreased　with　Tat　treatment.　SIRT1　activator　resveratrol　reversed　Tat-mediated　reduction　in　AMPK　activation　and　downstream　ACC　activation;　while　SIRT1　inhibitor　nicotinamide　or　knockdown　of　SIRT1　by　siRNA　potentiated　Tat-mediated　reduction　in　AMPK　activation　and　downstream　ACC　activation.　Consistent　with　this　association,　AMPK　activator　AICAR　as　well　as　resveratrol　inhibited　Tat-induced　HIV-1　transactivation.　On　the　contrary,　AMPK　inhibitor　compound　C,　knockdown　of　AMPK　by　siRNA　as　well　as　nicotinamide　or　knockdown　of　SIRT1　by　siRNA　potentiated　Tat-induced　HIV-1　transactivation.　Collectively,　our　data　provide　new　insights　into　understanding　of　the　molecular　mechanisms　of　Tat-regulated　transcription,　suggesting　that　targeting　SIRT1-AMPK　pathway　could　serve　as　a　new　target　for　the　development　of　new　anti　HIV-1　agents.　(C)　2009　Elsevier　B.V.　All　rights　reserved.