Vol. 52, Issue 6, 1157-1163, 1997

S-Adenosylhomocysteine Hydrolase Inhibitors Interfere with the Replication of Human Immunodeficiency Virus Type 1 through Inhibition of the LTR Transactivation

Dirk Daelemans, Jose A. Esté, Myriam Witvrouw, Christophe Pannecouque, Heidi Jonckheere, Stefano Aquaro, Carlo-Federico Perno, Erik De Clercq, and Anne-Mieke Vandamme

Rega Institute for Medical Research, Katholieke Universtiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium (D.D., J.A.E., M.W., C.P., H.J., E.D.C., A.-M.V.), and Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy (S.A., C.-F.P.)

Various analogues of adenosine have been described as inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, and some of these AdoHcy hydrolase 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-stimulated peripheral blood lymphocytes infected acutely or chronically with HIV-1_IIIB or HIV_BaL strains, a wide range of adenosine analogues did not inhibit HIV-1_IIIB replication for 50% at subtoxic concentrations. However, they inhibited HIV-1 replication in HeLa CD4⁺ LTR-LacZ cells at concentrations well below cytotoxicity threshold. A close correlation was found among the inhibitory effect of the compounds on AdoHcy hydrolase activity, their inhibition of HIV-1 replication in Hela CD4⁺ LTR-LacZ cells, and their inhibition of the HIV-1 Tat-dependent and -independent transactivation of the long terminal repeat, whereas no inhibitory effect was seen on HIV-1 reverse transcription or a Tat-independent cytomegalovirus promoter. Our results suggest that AdoHcy hydrolase and the associated S-adenosylmethionine-dependent methylation mechanism play a role in the process of long terminal repeat transactivation and, hence, HIV replication.