S-adenosylhomocysteine hydrolase inhibitors interfere with the replication of human immunodeficiency virus type 1 through inhibition of the LTR transactivation

Mol Pharmacol. 1997 Dec;52(6):1157-63. doi: 10.1124/mol.52.6.1157.

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-1IIIB or 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylhomocysteinase
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Enzyme Inhibitors / pharmacology*
  • Gene Products, tat / physiology
  • HIV Long Terminal Repeat*
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / physiology*
  • HeLa Cells / virology
  • Humans
  • Hydrolases / antagonists & inhibitors*
  • Hydrolases / physiology
  • Reverse Transcriptase Inhibitors / pharmacology
  • Transcriptional Activation / drug effects*
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / physiology
  • Virus Replication / drug effects*
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Gene Products, tat
  • Reverse Transcriptase Inhibitors
  • Viral Proteins
  • tat Gene Products, Human Immunodeficiency Virus
  • HIV Reverse Transcriptase
  • Hydrolases
  • Adenosylhomocysteinase