S-adenosylhomocysteine hydrolase inhibitors interfere with the replication of human immunodeficiency virus type 1 through inhibition of the LTR transactivation.
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.
Daelemans
D
D
Rega Institute for Medical Research, Katholieke Universtiteit Leuven, Belgium. dirk.daelemans@uz.kuleuven.ac.be
Esté
J A
JA
Witvrouw
M
M
Pannecouque
C
C
Jonckheere
H
H
Aquaro
S
S
Perno
C F
CF
De Clercq
E
E
Vandamme
A M
AM
D043383:Adenosylhomocysteinase; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015696:Gene Products, tat / Q000502:physiology; D016325:HIV Long Terminal Repeat; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D054303:HIV Reverse Transcriptase; D006867:Hydrolases; D043383:Adenosylhomocysteinase