Preferential selection of human T-cell leukemia virus type 1 provirus lacking the 5' long terminal repeat during oncogenesis.
In adult T-cell leukemia (ATL) cells, a defective human T-cell leukemia virus type 1 (HTLV-1) provirus lacking the 5' long terminal repeat (LTR), designated type 2 defective provirus, is frequently observed. To investigate the mechanism underlying the generation of the defective provirus, we sequenced HTLV-1 provirus integration sites from cases of ATL. In HTLV-1 proviruses retaining both LTRs, 6-bp repeat sequences were adjacent to the 5' and 3' LTRs. In 8 of 12 cases with type 2 defective provirus, 6-bp repeats were identified at both ends. In five of these cases, a short repeat was bound to CA dinucleotides of the pol and env genes at the 5' end, suggesting that these type 2 defective proviruses were formed before integration. In four cases lacking the 6-bp repeat, short (6- to 26-bp) deletions in the host genome were identified, indicating that these defective proviruses were generated after integration. Quantification indicated frequencies of type 2 defective provirus of less than 3.9% for two carriers, which are much lower than those seen for ATL cases (27.8%). In type 2 defective proviruses, the second exons of the tax, rex, and p30 genes were frequently deleted, leaving Tax unable to activate NF-kappaB and CREB pathways. The HTLV-1 bZIP factor gene, located on the minus strand, is expressed in ATL cells with this defective provirus, and its coding sequences are intact, suggesting its significance in oncogenesis.
Miyazaki
Maki
M
Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Shogoin Kawara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan.
Yasunaga
Jun-Ichirou
J
Taniguchi
Yuko
Y
Tamiya
Sadahiro
S
Nakahata
Tatsutoshi
T
Matsuoka
Masao
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology*; D008969:Molecular Sequence Data; D011533:Proviruses / Q000235:genetics*; D012191:Retroviridae Proteins; D020079:Terminal Repeat Sequences; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016662:Virus Integration / Q000235:genetics
D050976:Basic-Leucine Zipper Transcription Factors; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D014764:Viral Proteins