title: Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase.
abstract: Chemotherapy that is used to treat human immunodeficiency virus type-1 (HIV-1) infection focuses primarily on targeting virally encoded proteins. However, the combination of a short retroviral life cycle and high mutation rate leads to the selection of drug-resistant HIV-1 variants. One way to address this problem is to inhibit non-essential host cell proteins that are required for viral replication. Here we show that the activity of HIV-1 integrase stimulates an ataxia-telangiectasia-mutated (ATM)-dependent DNA damage response, and that a deficiency of this ATM kinase sensitizes cells to retrovirus-induced cell death. Consistent with these observations, we demonstrate that a novel and specific small molecule inhibitor of ATM kinase activity, KU-55933, is capable of suppressing the replication of both wild-type and drug-resistant HIV-1.
authors.affiliation: KuDOS Pharmaceuticals Limited, 327 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Karra M
authors.initials: KM
authors.lastname: Swinbank
authors.forename: Parvin S
authors.initials: PS
authors.lastname: Ahmed
authors.forename: Debra L
authors.initials: DL
authors.lastname: Taylor
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017320:HIV Protease Inhibitors; D009025:Morpholines; D011753:Pyrones; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D019427:HIV Integrase