S-ADENOSYLHOMOCYSTEINE HYDROLASE INHIBITORS INTERFERE WITH THE REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 THROUGH INHIBITION OF THELTR TRANSACTIVATION

Various analogues of adenosine have been described as inhibitors of S- adenosylhomocysteine (AdoHcy) hydrolase, and some of these AdoHcy hydr olase inhibitors (e.g., 3-deazaadenosine, 3-deazaaristeromycin, and 3- deazaneplanocin A) have also been reported to inhibit the replication of human immunodeficiency virus type 1 (HIV-1). When evaluated against HIV-1 replication in MT-4 cells, macrophages, or phytohemagglutinin-s timulated peripheral blood lymphocytes infected acutely or chronically with HIV-1(IIIB) or HIVBaL strains, a wide range of adenosine analogu es did not inhibit HIV-1(IIIB) replication for 50% at subtoxic concent rations. However, they inhibited HIV-1 replication in HeLa CD4(+) LTR- LacZ cells at concentrations well below cytotoxicity threshold. A clos e correlation was found among the inhibitory effect of the compounds o n AdoHcy hydrolase activity, their inhibition of HIV-1 replication in Hela CD4(+) LTR-LacZ cells, and their inhibition of the HIV-1 Tat-depe ndent and -independent transactivation of the long terminal repeat, wh ereas no inhibitory effect was seen on HIV-1 reverse transcription or a Tat-independent cytomegalovirus promoter. Our results suggest that A doHcy hydrolase and the associated S-adenosylmethionine-dependent meth ylation mechanism play role in the process of long terminal repeat tra nsactivation and, hence, HIV replication.