Dual biological activity of apurinic acid on human lymphocytes: induction of interferon-gamma and protection from human immunodeficiency virus infection in vitro.
The chemically modified DNA, apurinic acid (APA), is cytotoxic for human lymphocytes at concentrations above 100 micrograms/ml. At low concentrations (0.05-1 micrograms/ml) APA acts as an inducer interferon gamma (IFN-gamma) in lymphocytes in vitro; the maximum interferon titer of 50 units/ml was reached at 0.4 micrograms/ml. When added to the cells in combination with phytohemagglutinin A (PHA), APA displays a significant synergistic interferon-inducing ability; the maximum titer of 940 units/ml was obtained with 10 micrograms/ml of APA and 6.25 micrograms/ml of PHA. APA also proved to be an effective inhibitor of human immunodeficiency virus (HIV-1) replication in H9 cells. At a concentration of 10 micrograms/ml, APA causes a 49% inhibition of virus growth, while 20 micrograms/ml of APA are required to inhibit expression of HIV-1 p17 and p24 gag proteins by 60%. The mechanism of anti HIV-1 activity of APA likely occurs at the level of viral reverse transcriptase. This enzyme is inhibited by APA in a noncompetitive way with a Ki of 0.39 microM, while the cellular DNA polymerases alpha, beta and gamma are 140- to 300-fold less sensitive to APA.
Müller
W E
WE
Institut für Physiologische Chemie, Abt. Angewandte Molekularbiologie, Universität, Mainz, F.R.G.
Sarin
P S
PS
Sun
D
D
Rossol
S
S
Voth
R
R
Rottmann
M
M
Hess
G
G
Meyer zum Büschenfelde
K H
KH
Schröder
H C
HC
D001080:Apurinic Acid / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D011119:Polynucleotides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018894:Reverse Transcriptase Inhibitors
D010835:Phytohemagglutinins; D011119:Polynucleotides; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D001080:Apurinic Acid; D007371:Interferon-gamma