Human T-cell leukemia virus type 1 infection leads to arrest in the G1 phase of the cell cycle.
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.
Liu
Meihong
M
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Yang
Liangpeng
L
Zhang
Ling
L
Liu
Baoying
B
Merling
Randall
R
Xia
Zheng
Z
Giam
Chou-Zen
CZ
D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D018920:Coculture Techniques; D016193:G1 Phase / Q000502:physiology*; D015490:HTLV-I Infections / Q000821:virology; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology