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Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

Nature Cell Biology volume 7, pages 493–500 (2005)Cite this article

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.

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Figure 1: ATM function is required for efficient HIV-1 infection.
Figure 2: Functional HIV-1 integrase is required to elicit an ATM-dependent DNA damage response.
Figure 3: ATM-deficient cells show enhanced cell death when transduced with recombinant HIV-1 IN+ vectors.
Figure 4: Suppression of HIV-1 vector transduction by KU-55933.
Figure 5: Effect of KU-55933 on HIV-1 cDNA intermediate formation and integration.
Figure 6: Inhibition of HIV-1 replication by KU-55933.

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Acknowledgements

We would like to acknowledge the efforts of M. Hummersone, L. Rigoreau, I. Hickson and C. Richardson for their work on KU-55933. We would also like to thank M. Albertella and A. Jazayeri for their helpful comments.

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Authors and Affiliations

  1. KuDOS Pharmaceuticals Limited, 327 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK

    Alan Lau, Stephen P. Jackson, Graeme C. M. Smith & Mark J. O'Connor

  2. MRC Technology, 1–3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK

    Karra M. Swinbank, Parvin S. Ahmed & Debra L. Taylor

  3. The Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge, CB3 1QN, UK

    Stephen P. Jackson

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  1. Alan Lau
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Correspondence to Mark J. O'Connor.

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Competing interests

A.l., G.C.M.S. and M.O.C. are employees of Kudos Pharmaceuticals Ltd. S.P.J. is the scientific founder and chief scientific officer of Kudos Pharmaceuticals Ltd.

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Lau, A., Swinbank, K., Ahmed, P. et al. Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nat Cell Biol 7, 493–500 (2005). https://doi.org/10.1038/ncb1250

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