T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1

Franchini, Genoveffa; Fukumoto, Risaku; Fullen, Jake

doi:10.1007/bf02983552

Cited by 61 publications

(52 citation statements)

References 285 publications

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“…Their accessory genes elaborately control replication of genome copy (1). The HIV vigorously replicates to yield progeny virus, whereas human T cell leukemia virus type I (HTLV-I) increases the number of infected cells by the activity of accessory genes (2,3). HTLV-I was the first human retrovirus associated with human disease (4,5).…”

Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

“…To facilitate transmission, HTLV-I increases the number of infected cells through the activity of accessory genes, which are encoded by the pX region located between env and the 3Ј long terminal repeat (LTR). These genes include tax, rex, p30, p12, p13, and HTLV-I basic leucine zipper factor (HBZ) (3,8). Among them, tax is thought to play a central role in increasing the number of infected cells.…”

Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

“…Among them, tax is thought to play a central role in increasing the number of infected cells. Tax activates transcriptional pathways, including nuclear factor -B, cAMP response element-binding protein, activator protein-1, and serum responsive factor (2,3). In addition, Tax can functionally inactivate p53 (9), resulting in inhibition of apoptosis.…”

Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

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HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells

Satou

Yasunaga

Yoshida

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

523

744

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Human T cell leukemia virus type I (HTLV-I) causes adult T cell leukemia (ATL) in 2–5% of carriers after a long latent period. An HTLV-I encoded protein, Tax, induces proliferation and inhibits apoptosis, resulting in clonal proliferation of infected cells. However, tax gene expression in ATL cells is disrupted by several mechanisms, including genetic changes in the tax gene and DNA methylation/deletion of the 5′ long terminal repeat (LTR). Because Tax is the major target of cytotoxic T-lymphocytes in vivo , loss of Tax expression should enable ATL cells to escape the host immune system. The 5′ LTR of HTLV-I is frequently hypermethylated or deleted in ATL cells, whereas the 3′ LTR remains unmethylated and intact, suggesting the involvement of the 3′ LTR in leukemogenesis. Here we show that a gene encoded by the minus strand of the HTLV-I proviral genome, HTLV-I basic leucine zipper factor ( HBZ ), is transcribed from 3′-LTR in all ATL cells. Suppression of HBZ gene transcription by short interfering RNA inhibits proliferation of ATL cells. In addition, HBZ gene expression promotes proliferation of a human T cell line. Analyses of T cell lines transfected with mutated HBZ genes showed that HBZ promotes T cell proliferation in its RNA form, whereas HBZ protein suppresses Tax-mediated viral transcription through the 5′ LTR. Thus, the single HBZ gene has bimodal functions in two different molecular forms. The growth-promoting activity of HBZ RNA likely plays an important role in oncogenesis by HTLV-I.

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Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

Section: Fig 1 Hbz Gene Expression In Atl Cells (A) 5јmentioning

confidence: 99%

See 1 more Smart Citation

HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells

Satou

Yasunaga

Yoshida

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

523

744

View full text Add to dashboard Cite

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“…The tax gene plays a central role by its pleiotropic actions in the proliferation and leukemogenesis of HTLV-I-infected cells in vivo (Franchini et al, 2003). However, its transcription is detected in only 34% of ATL cases by RT-PCR (Takeda et al, 2004).…”

Section: Htlv-i Provirus In Atl Cellsmentioning

confidence: 99%

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

2005

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After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-a plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naı¨ve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficultto-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary.

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“…H uman T cell leukemia virus type 1 (HTLV-1) is a retrovirus that is epidemiologically associated with mature CD3 ϩ CD4 ϩ T cell-type leukemia͞lymphoma (ATL), as well as with tropical spastic paraparesis͞myelopathy (1,2). It is estimated that up to 30 million people worldwide are infected with HTLV, with ATL being particularly prevalent in Japan (3).…”

mentioning

confidence: 99%

Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design

Laco

Jaskólski

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The successful development of a number of HIV-1 protease (PR) inhibitors for the treatment of AIDS has validated the utilization of retroviral PRs as drug targets and necessitated their detailed structural study. Here we report the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substratebased inhibitor bound in subsites P5 through P5 . Although HTLV-1 PR exhibits an overall fold similar to other retroviral PRs, significant structural differences are present in several loop areas, which include the functionally important flaps, previously considered to be structurally highly conserved. Potential key residues responsible for the resistance of HTLV-1 PR to anti-HIV drugs are identified. We expect that the knowledge accumulated during the development of anti-HIV drugs, particularly in overcoming drug resistance, will help in designing a novel class of antileukemia drugs targeting HTLV-1 PR and in predicting their drug-resistance profile. The structure presented here can be used as a starting point for the development of such anticancer therapies.inhibitor ͉ leukemia ͉ retroviral protease H uman T cell leukemia virus type 1 (HTLV-1) is a retrovirus that is epidemiologically associated with mature CD3 ϩ CD4 ϩ T cell-type leukemia͞lymphoma (ATL), as well as with tropical spastic paraparesis͞myelopathy (1, 2). It is estimated that up to 30 million people worldwide are infected with HTLV, with ATL being particularly prevalent in Japan (3). Only an estimated 3-5% of people infected with the virus develop ATL in their lifetime, but for those that do, the prognosis is poor (4). Although a number of treatments for ATL, such as combination chemotherapy, monoclonal antibodies directed against the ␣ chain of the interleukin 2 receptor, and antiviral therapy involving IFN-␣ and zidovudine, are used clinically, they show only very limited efficacy (3). Novel approaches under investigation use proteasome inhibitors (5) and Tax-targeted immunotherapy (4), but they have not yet been tested in practice. It is clear that new anti-ATL targets need to be found.In common with other retroviruses, HTLV-1 encodes a protease (PR) necessary for its maturation. Because inhibition of the enzyme has been shown to prevent viral proliferation, development of inhibitors targeting HTLV-1 PR is an attractive new path for chemotherapy (6). HTLV-1 PR is a homodimer, with each chain containing 125 residues. The enzymatic properties of HTLV-1 PR, including its substrate specificity, have already been studied in considerable detail (7,8). Although the design and synthesis of inhibitors specific for HTLV-1 PR have been carried out, most of the compounds are active only in micromolar concentration (9, 10). The best statine-containing inhibitor has a K i of 50 nM under high-salt conditions (7) but of only 2.3 M in a low-salt buffer (11). In comparison, a number of subpicomolar inhibitors of HIV-1 PR have been developed by using the principles of rational drug design (12).Structural investigations of HTLV-1 PR have not been su...

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T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1

Cited by 61 publications

References 285 publications

HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells

HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design

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