Modulation of nuclear matrix-associated 2',5'-oligoadenylate metabolism and ribonuclease L activity in H9 cells by human immunodeficiency virus.
Human T cells (H9), infected with the HTLV-IIIB strain of the human immunodeficiency virus (HIV-1), have been used to study the alteration of 2',5'-oligoadenylate [2'-5')A) metabolism in relation to virus production. The synthesis of (2'-5')A was determined to proceed in close association with the nuclear matrix. After HIV infection the (2'-5')A synthetase activity increased from 1.1 to 1.5 pmol of (2'-5')A synthesized/100 micrograms of nuclear matrix protein (during a 3-h in vitro incubation period) to 8.2 pmol at day 3 after infection. Then the activity dropped to the initial values. In non-infected H9 cells the (2'-5')A synthetase activity remained unchanged. Simultaneously with the decrease of the (2'-5')A level the cells started to release HIV. At the time of maximum synthetase levels the (2'-5')A-activated endoribonuclease (RNase L) activity strongly increased. Only one protein could be selectively cross-linked to a (2'-5')A derivative in the nuclear matrix from H9 cells; this protein is assumed to be RNase L. Experimental evidence is provided revealing that RNase L degrades HIV transcripts. A correlation could be established between high levels of (2'-5')A and RNase L and a failure of the cells to release HIV. 3'-Azido-3'-deoxythymidine was shown to cause an extension of the time period during which an RNase L-mediated degradation of viral transcripts occurred. The possibility of a novel molecular pharmacologic approach on the level of (2'-5')A metabolism is discussed.
Schröder
H C
HC
Institut für Physiologische Chemie, Universität, Mainz, West Germany.
Wenger
R
R
Kuchino
Y
Y
Müller
W E
WE
D000227:Adenine Nucleotides / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002472:Cell Transformation, Viral; D004722:Endoribonucleases / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D009843:Oligoribonucleotides / Q000378:metabolism*; D012332:RNA, Heterogeneous Nuclear / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease