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Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase |
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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.
Mammalian cells encounter a variety of DNA-damaging agents and possess a number of different response pathways to maintain genomic integrity1. One of the less well defined DNA damage responses results from retroviral infections such as those induced by HIV-1. Integration of the double-stranded cDNA reverse transcriptase product into the host genome is an essential step in the retroviral life cycle. This event is catalysed in part by the viral integrase protein that cleaves the host DNA and promotes a strand transfer reaction resulting in short staggered DNA breaks at the site of attachment2.
The gapped DNA intermediates then have to be detected and efficiently repaired by host cell proteins if there is to be a completed integration process and a productive infection. In addition, it has been suggested that the unintegrated linear viral cDNA may itself invoke a DNA damage response that, if left unchecked, will result in the death of the host cell. This raises the possibility that the inhibition of host DNA damage response factors could provide a new therapeutic approach for the treatment of HIV-1 infections, especially because some of these factors are not essential for cell survival.
A number of groups have provided evidence that the Ku-dependent non-homologous end-joining (NHEJ) pathway that is normally associated with the repair of DNA double-strand breaks (DSBs) is required to support efficient retroviral infection3, 4, 5, 6 and to prevent viral-induced cell death3, 4. However, there is some controversy as to whether cell death following retroviral infection is dependent on integrase activity3, 4. Additional questions have also been raised about the involvement of the ATM and ataxia-telangiectasia- and Rad3-related (ATR) proteins in retroviral-induced DNA damage responses7, 8. Both ATM and ATR are phosphatidylinositol-3-OH-kinase (PI(3)K)-like serine/threonine kinases (PIKKs) that regulate cellular responses to DNA damage by controlling cell-cycle arrest and DNA repair pathways9, 10. Although many of the protein substrates of ATM and ATR overlap9, activation of the ATM or ATR kinases largely depends on the type of DNA damage lesion and the stage of the cell cycle in which it is encountered. ATM predominantly detects DNA DSBs, such as those caused by ionizing radiation, and responds very rapidly to these lesions at all stages of the cell cycle, whereas ATR is activated by agents such as ultraviolet radiation and replication-fork collapse during S phase10.
Here, by using both genetic and pharmacological approaches, we demonstrate that ATM activity has an important role in retroviral replication. By screening a small molecule compound library developed for the PIKK family, we have identified KU-55933, a novel, specific and potent inhibitor of ATM11. This compound, which is not effective in targeting ATR, DNA-dependent protein kinase (DNA-PK) or PI(3)K, suppresses HIV-1 replication and provides important proof of concept that the inhibition of ATM, a non-essential cellular target, may represent a new approach to the treatment of HIV-1 infections.
Click here for full article : http://www.nature.com/cgi-taf/DynaPage.taf?file=/ncb/journal/v7/n5/full/ncb1250.html |
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Last Updated ( Saturday, 14 May 2005 )
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