Abstract
Various analogues of adenosine have been described as inhibitors ofS-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-1IIIBor HIVBaL strains, a wide range of adenosine analogues did not inhibit HIV-1IIIB 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.
Footnotes
- Received June 6, 1997.
- Accepted September 10, 1997.
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Send reprint requests to: Dirk Daelemans, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: dirk.daelemans{at}uz.kuleuven.ac.be
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This work was supported in part by the Biomedical Research Program of the European Union (Biomed 2 Grant BMH4-LT-951634), the Belgian Geconcerteerde Onderzoeksacties (Project GOA 95/5), and a grant from the “Fonds voor Wetenschappelijk Onderzoek (FWO), Vlaanderen” (Grant G.3304396). D.D. acknowledges a grant from the Flemisch Institute supporting Scientific-Technological Research in Industry (IWT).
- The American Society for Pharmacology and Experimental Therapeutics
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