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Journal of Virology, March 2002, p. 2692-2702, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2692-2702.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Nef Binds to Tumor Suppressor p53 and Protects Cells against p53-Mediated Apoptosis

Alison L. Greenway,1* Dale A. McPhee,1,2 Kelly Allen,1 Ricky Johnstone,3 Gavan Holloway,1 John Mills,2 Ahmed Azad,4 Sonia Sankovich,4 and Paul Lambert5

AIDS Cellular Biology Unit,1 AIDS Molecular Biology Unit, Macfarlane Burnet Centre for Medical Research,5 National Centre in HIV Virology Research, Fairfield, Victoria 3078,2 Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002,3 Biomolecular Research Institute, Parkville, Victoria 3052, Australia4

Received 25 October 2001/ Accepted 17 December 2001

The nef gene product of human immunodeficiency virus type 1 (HIV-1) is important for the induction of AIDS, and key to its function is its ability to manipulate T-cell function by targeting cellular signal transduction proteins. We reported that Nef coprecipitates a multiprotein complex from cells which contains tumor suppressor protein p53. We now show that Nef interacts directly with p53. Binding assays showed that an N-terminal, 57-residue fragment of Nef (Nef 1-57) contains the p53-binding domain. Nef also interacted with p53 during HIV-1 infection in vitro. As p53 plays a critical role in the regulation of apoptosis, we hypothesized that Nef may alter this process. Nef inhibited UV light-induced, p53-dependent apoptosis in MOLT-4 cells, with Nef 1-57 being as effective as its full-length counterpart. The inhibition by Nef of p53 apoptotic function is most likely due its observed ability to decrease p53 protein half-life and, consequently, p53 DNA binding activity and transcriptional activation. These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis.

* Corresponding author. Mailing address: AIDS Cellular Biology Unit, Macfarlane Burnet Centre for Medical Research, Yarra Bend Rd., Fairfield, Victoria 3078, Australia. Phone: 61-3 9282 2112. Fax: 61-3 9282 2100. E-mail: greenway{at}burnet.edu.au.

Journal of Virology, March 2002, p. 2692-2702, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2692-2702.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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