The 2-5A system and HIV infection.
2',5'-Oligoadenylates (2-5A) have an essential role in the establishment of the antiviral state of a cell exposed to virus infection. The key enzymes of the 2-5A system are the 2-5A forming 2',5'-oligoadenylate synthetase (2-5OAS), the activity of which depends on the presence of viral or cellular double-stranded RNA (dsRNA), and the 2-5A-activated ribonuclease (RNase L). Basic research in recent years has shown that the 2-5A system is a promising target for anti-HIV chemotherapy, particularly due to its interaction with double-stranded segments within HIV RNA. Two new strategies have been developed which yield a selective antiviral effect of 2-5A against HIV-1 infection: (1) development of 2-5A analogues displaying a dual mode of action (activation of RNase L and inhibition of HIV-1 RT) and (2) intracellular immunization of cells against HIV-1 infection by application of the HIV-1-LTR--2-5OAS hybrid gene. A further strategy is the inhibition of DNA topoisomerase I by longer 2-5A oligomers.
Schröder
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Abteilung Angewandte Molekularbiologie, Johannes Gutenberg-Universität, Mainz, Germany.
Kelve
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Müller
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D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000386:AIDS-Related Complex / Q000188:drug therapy / Q000378:metabolism; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000378:metabolism* / Q000633:toxicity; D000998:Antiviral Agents / Q000633:toxicity; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D002628:Chemoreceptor Cells; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D029968:Escherichia coli Proteins; D015696:Gene Products, tat / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009843:Oligoribonucleotides / Q000378:metabolism* / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface; D013873:Thionucleotides / Q000633:toxicity; D019892:eIF-2 Kinase; D054322:tat Gene Products, Human Immunodeficiency Virus
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D015696:Gene Products, tat; D008565:Membrane Proteins; D009843:Oligoribonucleotides; D011956:Receptors, Cell Surface; C057331:Tar protein, E coli; D013873:Thionucleotides; D054322:tat Gene Products, Human Immunodeficiency Virus; C023505:2',5'-oligoadenylate; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease