Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase (Nature Cell Biology, 7:493-500, May 2005)

報告日期: 2005/09/20
報告時間: 16:00/16:50
報告學生: 葉明德
講評老師: 王憲威
附件下載:

Suppression of HIV-1 Infection by a Small Molecule Inhibitor of the ATM Kinase

Alan Lau,Karra M. Swinbank, Parvin S. Ahmed, Debrra L. Taylor, Stephen P. Jackson, Graeme C. M. Smith and Mark J. O’Connor

Nature Cell Biology, 7:493-500, 2005

 

Speaker: Mingte YEH                                                     Time: 2005/9/20 16:10-17:00

Commentator:

Dr. Shainn-Wei WANG                            Place
: Room602

 

Abstract:

Current antiviral drugs against HIV-1 target primarily on viral proteins such as reverse transcriptase and protease. However, the appearance of drug-resistant strains has limited the success of these approaches. In this study, a new therapeutic approach against HIV-1 target on cellular proteins that are required for the retroviral life cycle is presented. Integration of reverse-transcribed viral double-stranded DNA into a host cell’s genome is an essential step in the retroviral life cycle and is required for the productive replication of the virus. The integration process is initiated and directed by the viral integrase protein. Integrase removes two terminal 3¢ nucleotides at each end of the viral linear DNA, exposing recessed 3¢ hydroxyl groups and then catalyzes a nucleophilic attack of the recessed 3¢ hydroxyl groups on phosphodiester bonds in each target cellular DNA strand. The initial linkage between the viral and cellular DNA is a gapped integration intermediate with unlinked viral 5¢-ends. For the integration process to be completed, the gaps have to be efficiently detected and repaired by host DNA repair machinery. Among the components of the host DNA repair machinery, ATM (Ataxia-Telangiectaxia-Mutated), a protein kinase member of phosphatidylinositol 3¢-kinase (PI3K)-related kinase (PIKK) family, plays a major role in sensing and triggering the repair of DNA lesions in mammalian cells and hence represent a potential therapeutic target. By the use of a specific inhibitor of ATM kinase, KU-55933, it is demonstrated that ATM is required for efficient HIV-1 infection and ATM deficiency sensitizes cells to HIV-1 induced cell death. It is also demonstrated that KU-55933 inhibits drug-resistant HIV-1 as efficiently as wild-type virus. Taken together, this study provides evidence that inhibition of cellular proteins required for viral life cycle could be a new approach for the treatment of HIV-1

infection.

 

References:

1.         Asante-Appiah, E., and Skalka, A. M. (1997). Molecular mechanisms in retrovirus DNA integration. Antiviral Res 36, 139-156.

2.         McKinnon, P. J. (2004). ATM and ataxia telangiectasia. EMBO Rep 5, 772-776.

3.         Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3, 155-168.