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, Anne Mieke Vandamme

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Abstract

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.

Original languageEnglish
Pages (from-to)1157-1163
Number of pages7
JournalMolecular Pharmacology
Volume52
Issue number6
Publication statusPublished - Dec 1997

ASJC Scopus subject areas

  • Pharmacology

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    Daelemans, D., Esté, J. A., Witvrouw, M., Pannecouque, C., Jonckheere, H., Aquaro, S., Perno, C. F., De Clercq, E., & Vandamme, A. M. (1997). S-adenosylhomocysteine hydrolase inhibitors interfere with the replication of human immunodeficiency virus type 1 through inhibition of the LTR transactivation. Molecular Pharmacology, 52(6), 1157-1163.