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

• Published in: Journal of virology 2008-09, Vol.82 (17), p.8442-8455
• Main Authors: Liu, Meihong, Yang, Liangpeng, Zhang, Ling, Liu, Baoying, Merling, Randall, Xia, Zheng, Giam, Chou-Zen
• Format: Article
• Language: English
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.00091-08

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 G 1 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 G 1 arrest to be bypassed. Finally, HTLV-1 infection and Tax expression also cause human SupT1 T cells to arrest in the G 1 phase of the cell cycle. These results suggest that productive HTLV-1 infection ordinarily leads to Tax-mediated G 1 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.