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Journal of Virology, September 2008, p. 8442-8455, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00091-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human T-Cell Leukemia Virus Type 1 Infection Leads to Arrest in the G₁ Phase of the Cell Cycle

Meihong Liu,^1, Liangpeng Yang,^1, Ling Zhang,¹ Baoying Liu,² Randall Merling,¹ Zheng Xia,¹ and Chou-Zen Giam^1*

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland 20814,¹ Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892²

Received 14 January 2008/ Accepted 19 June 2008

Infection by the human T-cell leukemia virus type 1 (HTLV-1) is thought to cause dysregulated T-cell proliferation, which in turn leads to adult T-cell leukemia/lymphoma. Early cellular changes after HTLV-1 infection have been difficult to study due to the poorly infectious nature of HTLV-1 and the need for cell-to-cell contact for HTLV-1 transmission. Using a series of reporter systems, we show that HeLa cells cease proliferation within one or two division cycles after infection by HTLV-1 or transduction of the HTLV-1 tax gene. HTLV-1-infected HeLa cells, like their tax-transduced counterparts, expressed high levels of p21^CIP1/WAF1 and p27^KIP1, developed mitotic abnormalities, and became arrested in G₁ in senescence. In contrast, cells of a human osteosarcoma lineage (HOS) continued to divide after HTLV-1 infection or Tax expression, albeit at a reduced growth rate and with mitotic aberrations. Unique to HOS cells is the dramatic reduction of p21^CIP1/WAF1 and p27^KIP1 expression, which is in part associated with the constitutive activation of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway. The loss of p21^CIP1/WAF1 and p27^KIP1 in HOS cells apparently allows HTLV-1- and Tax-induced G₁ arrest to be bypassed. Finally, HTLV-1 infection and Tax expression also cause human SupT1 T cells to arrest in the G₁ phase of the cell cycle. These results suggest that productive HTLV-1 infection ordinarily leads to Tax-mediated G₁ arrest. However, T cells containing somatic mutations that inactivate p21^CIP1/WAF1 and p27^KIP1 may continue to proliferate after HTLV-1 infection and Tax expression. These infected cells can expand clonally, accumulate additional chromosomal abnormalities, and progress to cancer.

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* Corresponding author. Mailing address: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-9624. Fax: (301) 295-1545. E-mail: cgiam{at}usuhs.mil

Published ahead of print on 2 July 2008.

The first two authors contributed equally to the paper.

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Journal of Virology, September 2008, p. 8442-8455, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00091-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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