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

  1. Dirk Daelemans1,
  2. Jose A. Esté1,
  3. Myriam Witvrouw1,
  4. Christophe Pannecouque1,
  5. Heidi Jonckheere1,
  6. Stefano Aquaro2,
  7. Carlo-Federico Perno2,
  8. Erik De Clercq1 and
  9. Anne-Mieke Vandamme1
  1. 1Rega 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 2Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy (S.A., C.-F.P.)

    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

    • 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

    • 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).

    • Abbreviations:
      AdoHcy
      S-adenosylhomocysteine
      AdoMet
      S-adenosylmethionine
      β-Gal
      β-galactosidase
      CC50
      50% cytotoxic concentration
      C-c3Ado
      carbocyclic 3-deazaadenosine
      DHCaA
      9-(trans-2,trans-3-dihydroxycyclopentyl)adenine
      c3DHCaA
      9-(trans-2,trans-3-dihydroxycyclopentyl)-3-deazaadenine
      c7DHCaA
      9-(trans-2,trans-3-dihydroxycyclopentyl)-7-deazaadenine
      DHPA
      9-(2,3-dihydroxypropyl)adenine
      Hcy
      homocysteine
      HIV-1
      human immunodeficiency virus type 1
      LTR
      long terminal repeat
      NKO-6–16-3
      3-deaza-3-fluoro-adenosine, NOM-14–6-1, 3-deaza-3-chloro-adenosine, NPA, neplanocin A
      c3NPA
      3-deazaneplanocin A
      PBL
      peripheral blood lymphocyte
      TAR
      transactivation response element
      TNF-α
      tumor necrosis factor-α
      RT
      reverse transcription
      • Received June 6, 1997.
      • Accepted September 10, 1997.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology December 1, 1997 vol. 52 no. 6 1157-1163
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology