Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia.

Adult T-cell leukemia (ATL), an aggressive neoplasm of mature helper T cells, is etiologically linked with human T lymphotropic virus type I (HTLV-1). After infection, HTLV-I randomly integrates its provirus into chromosomal DNA. Since ATL is the clonal proliferation of HTLV-I-infected T lymphocytes, molecular methods facilitate the detection of clonal integration of HTLV-I provirus in ATL cells. Using Southern blot analyses and long polymerase chain reaction (PCR) we examined HTLV-I provirus in 72 cases of ATL, of various clinical subtypes. Southern blot analyses revealed that ATL cells in 18 cases had only one long terminal repeat (LTR). Long PCR with LTR primers showed bands shorter than for the complete virus (7.7 kb) or no bands in ATL cells with defective virus. Thus, defective virus was evident in 40 of 72 cases (56%). Two types of defective virus were identified: the first type (type 1) defective virus retained both LTRs and lacked internal sequences, which were mainly the 5' region of provirus, such as gag and pol. Type 1 defective virus was found in 43% of all defective viruses. The second form (type 2) of defective virus had only one LTR, and 5'-LTR was preferentially deleted. This type of defective virus was more frequently detected in cases of acute and lymphoma-type ATL (21/54 cases) than in the chronic type (1/18 cases). The high frequency of this defective virus in the aggressive form of ATL suggests that it may be caused by the genetic instability of HTLV-I provirus, and cells with this defective virus are selected because they escape from immune surveillance systems.

[1]  G. Franchini.  Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection. , 1995, Blood.

[2]  M. Maki,et al.  Analysis of a novel defective HTLV‐I provirus and detection of a new HTLV‐I‐induced cellular transcript , 1995, FEBS letters.

[3]  M. Tomonaga,et al.  Homozygous deletions of the p15 (MTS2) and p16 (CDKN2/MTS1) genes in adult T-cell leukemia. , 1995, Blood.

[4]  M. Yoshida,et al.  Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells. , 1995, Blood.

[5]  M. Matsuoka,et al.  A novel diagnostic method of adult T-cell leukemia: monoclonal integration of human T-cell lymphotropic virus type I provirus DNA detected by inverse polymerase chain reaction , 1994 .

[6]  R. Schlegel,et al.  The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase , 1993, Journal of virology.

[7]  H. Koeffler,et al.  Mutations of the p53 gene in adult T-cell leukemia. , 1992, Blood.

[8]  M. Shimoyama,et al.  Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphoma , 1991, British journal of haematology.

[9]  B. Korber,et al.  Polymerase chain reaction analysis of defective human T-cell leukemia virus type I proviral genomes in leukemic cells of patients with adult T-cell leukemia , 1991, Journal of virology.

[10]  M. Kikuchi,et al.  Defective provirus form of human T-cell leukemia virus type I in adult T-cell leukemia/lymphoma: clinicopathological features. , 1991, Cancer research.

[11]  H. Inoko,et al.  Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells. , 1991, International immunology.

[12]  A. Fauci,et al.  Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease , 1990, Nature.

[13]  K. Yamaguchi,et al.  Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene , 1990, The Journal of experimental medicine.

[14]  R. Pirtle,et al.  A human tRNA gene heterocluster encoding threonine, proline and valine tRNAs. , 1989, Gene.

[15]  T. Sugimura,et al.  Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Karpas,et al.  Molecular cloning and complete nucleotide sequence of an adult T cell leukaemia virus/human T cell leukaemia virus type I (ATLV/HTLV-I) isolate of Caribbean origin: relationship to other members of the ATLV/HTLV-I subgroup. , 1988, The Journal of general virology.

[17]  K. Yamaguchi,et al.  Polyclonal integration of HTLV‐I proviral DNA in lymphocytes from HTLV‐I seropositive individuals: an intermediate state between the healthy carrier state and smouldering ATL , 1988, British journal of haematology.

[18]  T. Taniguchi,et al.  Induction of interleukin 2 receptor gene expression by p40x encoded by human T‐cell leukemia virus type 1. , 1986, The EMBO journal.

[19]  H. Yoshikura,et al.  Frequent partial deletion of human adult T-cell leukemia virus type I proviruses in experimental transmission: pattern and possible implication , 1986, Journal of virology.

[20]  T. Taniguchi,et al.  Expression of the pX gene of HTLV-I: general splicing mechanism in the HTLV family. , 1985, Science.

[21]  M. Yoshida,et al.  Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Sodroski,et al.  Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. , 1984, Science.

[23]  R. Eddy,et al.  Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells , 1984, Nature.

[24]  K. Yamaguchi,et al.  The detection of human T cell leukemia virus proviral DNA and its application for classification and diagnosis of T cell malignancy. , 1984, Blood.

[25]  K. Yamaguchi,et al.  Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Yoshida,et al.  Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Gelmann,et al.  A survey of human leukaemias for sequences of a human retrovirus , 1983, Nature.

[28]  M. Yoshida,et al.  Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[29]  John D. Minna,et al.  Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma , 1980, Proceedings of the National Academy of Sciences.

[30]  J. Yodoi,et al.  Adult T-cell leukemia: clinical and hematologic features of 16 cases. , 1977, Blood.

[31]  M. Matsuoka,et al.  Adult T-cell leukemia in Japan. , 1996, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[32]  M. Maki,et al.  Long cellular repeats flanking a defective HTLV-I provirus: implication for site-targeted integration. , 1993, Oncogene.

[33]  M. Feinberg,et al.  Molecular analysis of a deletion mutant provirus of type I human T-cell lymphotropic virus: evidence for a doubly spliced x-lor mRNA. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Yoshida,et al.  Molecular biology of human T-cell leukemia virus associated with adult T-cell leukemia. , 1985, Current topics in microbiology and immunology.

[35]  H. Towler,et al.  Adult T-cell leukemia : antigen in an ATL cell line and detection of antibodies to the antigen in human sera , 2022 .