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Journal of Virology, June 2000, p. 5040-5052, Vol. 74, No. 11
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Loss of G1/S Checkpoint in Human Immunodeficiency Virus Type 1-Infected Cells Is Associated with a Lack of Cyclin-Dependent Kinase Inhibitor p21/Waf1

Elizabeth Clark,1 Francisco Santiago,1 Longwen Deng,1 Siew yen Chong,1 Cynthia de la Fuente,1 Lai Wang,1 Peng Fu,1 Dana Stein,2 Thomas Denny,2 Venkata Lanka,1 Fariba Mozafari,3 Takashi Okamoto,4 and Fatah Kashanchi1,*

Department of Biochemistry and Molecular Biology1 and Department of Pathology and Pediatrics,2 University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103; Department of Hepatitis and Retroviruses, Pasteur Institute, Tehran, Iran3; and Department of Microbiology, Fukushima Medical College, Fukushima, Japan4

Received 27 August 1999/Accepted 28 February 2000

Productive high-titer infection by human immunodeficiency virus type 1 (HIV-1) requires the activation of target cells. Infection of quiescent peripheral CD4 lymphocytes by HIV-1 results in incomplete, labile reverse transcripts and lack of viral progeny formation. An interplay between Tat and p53 has previously been reported, where Tat inhibited the transcription of the p53 gene, which may aid in the development of AIDS-related malignancies, and p53 expression inhibited HIV-1 long terminal repeat transcription. Here, by using a well-defined and -characterized stress signal, gamma irradiation, we find that upon gamma irradiation, HIV-1-infected cells lose their G1/S checkpoints, enter the S phase inappropriately, and eventually apoptose. The loss of the G1/S checkpoint is associated with a loss of p21/Waf1 protein and increased activity of a major G1/S kinase, namely, cyclin E/cdk2. The p21/Waf1 protein, a known cyclin-dependent kinase inhibitor, interacts with the cdk2/cyclin E complex and inhibits progression of cells into S phase. We find that loss of the G1/S checkpoint in HIV-1-infected cells may in part be due to Tat's ability to bind p53 (a known activator of the p21/Waf1 promoter) and sequester its transactivation activity, as seen in both in vivo and in vitro transcription assays. The loss of p21/Waf1 in HIV-1-infected cells was specific to p21/Waf1 and did not occur with other KIP family members, such as p27 (KIP1) and p57 (KIP2). Finally, the advantage of a loss of the G1/S checkpoint for HIV-1 per se may be that it pushes the host cell into the S phase, which may then allow subsequent virus-associated processes, such as RNA splicing, transport, translation, and packaging of virion-specific genes, to occur.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, MSB-E635, Newark, NJ 07103. Phone: (973) 972-1089. Fax: (973) 972-1172. E-mail: kashanfa{at}umdnj.edu.

Journal of Virology, June 2000, p. 5040-5052, Vol. 74, No. 11
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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