Human t cell leukemia virus

You can help advance rare disease research! This site is in-development and may not reflect the final version. Preview the new GARD site. Other Names:. Viral infections. Summary Summary. Symptoms Symptoms. The signs and symptoms of this condition and the disease progression vary from person to person. Signs and symptoms of this condition vary but may include: [2] [3] Progressive weakness Stiff muscles Muscle spasms Backache 'Weak' bladder Constipation.

Do you have updated information on this disease? We want to hear from you. Cause Cause. Human T- cell leukemia virus , type 1 HTLV-1 occurs when a person is infected by the human T-cell leukemia retrovirus.

HTLV-1 is spread by blood transfusions, sexual contact and sharing needles. It can also be spread from mother to child during birth or breast-feeding. Diagnosis Diagnosis. Human T- cell leukemia virus , type 1 HTLV-1 is usually diagnosed based on blood tests that detect antibodies to the virus. Treatment Treatment. Abstract After experimental infection of squirrel monkeys Saimiri sciureus with human T-cell leukemia virus type 1 HTLV-1 -infected cells, the virus is transcribed only transiently in circulating blood, spleen, and lymph nodes.

Publication types Research Support, Non-U. A key cellular checkpoint is enforced by the p53 protein. Many cancer causing viruses have evolved multifaceted mechanisms to inactivate p53 Soria et al. Nevertheless, in the absence of genetic mutation of p53 , the p53 checkpoint is functionally inactivated in HTLV-1 infected cells by the Tax protein Reid et al.

How p53 is mechanistically inactivated in ATL remains incompletely clarified. Several redundant mechanisms Ariumi et al. It is also currently unanswered whether cellular phosphatases such as Wip1 Lindqvist et al. ATL cells are highly aneuploid Yasunaga and Jeang, A spindle assembly checkpoint SAC normally operates in mitosis to preserve euploidy by monitoring the fidelity of mitotic chromosomal segregation Chi and Jeang, It has been noted that SV40 Hein et al. DNA damage induced by Tax Majone et al.

In principle, damaged DNA can be created in two ways. First, the oncoprotein can attenuate damage sensing checkpoint and repair proteins. Second, the oncoprotein can directly elicit DNA lesions. Similarly, Tax also suppresses nucleotide excision repair Kao and Marriott, ; Lemoine et al.

In addition to allowing the persistence of genetic lesions, Tax was recently found to also induce reactive oxygen species, which can directly create damaged DNA Kinjo et al. Tax induction of reactive oxygen species is consistent with similar reactive oxygen species-induction by other viral transforming proteins, such as Ras Lee et al.

Collectively, the creation of new DNA damage and the prevention of ambient repair lead to a picture of significant clastogenic damage as reported for Tax-expressing cells Majone and Jeang, Various cancers have different miRNA signatures Lu et al. As the experimental settings were different, there was considerable discordance in the individual miRNA changes that were reported Ruggero et al.

Thus, Yeung et al. Taken together, the perturbation of oncogenic miRNAs in ATL may represent an additional multifaceted factor that needs to be considered for in vivo leukemogenesis. Mutational analyses of this promoter region show that three Sp1 sites are critical for HBZ transcription Yoshida et al. As the expression of Sp1 is relatively constant in most cells, Hbz gene expression is well correlated with the amount of integrated provirus in HTLVinfected individuals Saito et al.

The two pathways differentially control genes with anti-apoptotic functions in lymphoma cell lines Bernal-Mizrachi et al. Moreover, it has been shown that an HTLV-1 molecular clone with a mutation in the leucine zipper domain of HBZ, exhibited reduced proviral load compared with wild-type virus when inoculated into rabbits Arnold et al. Collectively, the extant data support that HBZ protein and Hbz RNA have roles in promoting viral replication and cellular proliferation.

One potential way to interpret the interplay between Tax and HBZ is that the former is needed to initiate transformation while the latter is required to maintain the transformed phenotype late in ATL when Tax expression is extinguished. In many ways, ATL is a poorly treatable disease. Patients with acute or lymphoma-type ATL are usually addressed with combination chemotherapy Figure 4. The major obstacles in therapy are the drug resistance of ATL cells to chemotherapeutic agents and the profoundly weakened and immunodeficient state of ATL patients.

The cause of ATL immunodeficiency may be from the immunosuppressive function of ATL cells, as they appear to arise from regulatory T cells Karube et al. As noted above, ATL immunodeficiency leads to complications from various opportunistic fungal, viral, protozoal and bacterial infections, which can worsen the prognosis.

Therapeutic approaches for ATL. Allogeneic stem cell transplantation has been shown to be effective in ATL patients Utsunomiya et al. It should be noted that provirus load remarkably decreased in many patients who received SCT.

The findings suggest that cell-mediated immunity to HTLV-1 was augmented in these patients, which might account for the efficacy of this therapy.

The presence of graft-versus-host disease is a good prognostic factor for ATL patients Okamura et al. In allogeneic stem cell transplantation treated individuals, CTLs to Tax peptides were activated in the recipients; and provirus load became profoundly suppressed, indicating the role of anti-HTLV-1 immune responses in the efficacious outcome Harashima et al.

Nevertheless, it remains unknown whether CTLs to Tax are required for the efficacy of stem cell transplantation therapy. Among 15 patients treated with KW, 5 patients achieved positive objective responses: 2 complete and 3 partial responses. Potentially, the KW antibody could be beneficial when combined with rituximab treatment. It has been reported that the mean survival time of patients with indolent subtypes, chronic and smoldering ATL was 4.

This finding shows that the prognosis of indolent ATL is poorer than previously thought Takasaki et al. Experiments using animal models have provided important information on therapeutic strategies for ATL patients. For example, monoclonal antibodies to CD25 Phillips et al.

In addition, it has been reported that a proteasome inhibitor, bortezomib, suppresses tumor formation of ATL cells in vivo Tan and Waldmann, ; Mitra-Kaushik et al.

These findings suggest the potential efficacy of these compounds and antibodies although they remain to be verified in clinical studies. Recent developments suggest that cancers, whether solid tumors for example, breast and lung or hematological malignancies for example, leukemia , are comprised of two categories of cells: those with high- and those with limited-proliferative potential.

Cells in the former category are termed cancer stem cells. Cancer stem cells share several properties with adult stem cells, particularly the abilities to self-renew and differentiate into multiple cell types. Cancer stem cells are found in a given cancer as a small sub-population; and cancer stem cells are reasoned to be the moieties, which cause disease relapse and metastasis.

They, unlike the bulk of tumor cells, are postulated to be the only cells capable of giving rise to new tumors. Success in the latter attempts would point to factors that are expressed in undifferentiated, rather than differentiated, cells that may be critical to ATL leukemogenesis.

Certainly, we expect these answers to be forthcoming in the next 30 years of HTLV-1 research. Oncogene 12 : — Oncogene 19 : — Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation.

Blood : — Hematopoietic stem cells and retroviral infection. Retrovirology 7 : 8. Stem Cells 26 : — J Biol Chem : — CAS Google Scholar. J Clin Oncol 28 : — Epub Jun A follow-up study of morbidity and mortality associated with hepatitis C virus infection and its interaction with human T lymphotropic virus type I in Miyazaki, Japan. J Infect Dis : 35— Bouzar AB, Willems L. Retrovirology 5 : Retrovirology 3 : Oncogene 17 : 77— J Virol 82 : — Aneuploidy and cancer.

J Cell Biochem : — Stable ubiquitination of human T-cell leukemia virus type 1 tax is required for proteasome binding. J Virol 78 : — IKKgamma mediates the interaction of cellular IkappaB kinases with the tax transforming protein of human T cell leukemia virus type 1. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10 : — J Virol 77 : — Site-specific phosphorylation differentiates active from inactive forms of the human T-cell leukemia virus type 1 Tax oncoprotein.

The hbz gene is continuously expressed in all HTLV-1 infected subjects thoughout infection, and it is only weakly immunogenic. It has weak transforming activity, independent of Tax, and it has been proposed to be a tumor maintenance factor. The hbz RNAs include spliced and unspliced forms that promote T cell proliferation, independent of their coding capacity. Thus, HBZ inhibits apoptosis, autophagy, inflammation, and disrupts genomic integrity. HBZ counteracts many of the functions of Tax, thus maintaining a persistent latent infection.

Genomic analysis of ATLL cases identified a high rate of mutations 2. These findings suggest that HTLV-1 infected cells develop mutations in these key oncogenic pathways survive and proliferate despite immunological selection for low levels of Tax expression. The figure depicts percentage of cases in which eachin the pathways is mutated in ATLL. Reprinted with permission from reference This research was originally published in Journal of Biological Chemistry.

Oncoproteins of human tumor viruses regularly interact with the cellular epigenetic machinery Tax activates expression of the genes for arginine and histone methyltransferases, and silences histone deacetylase 1 HDAC1 gene expression. Epigenetic regulatory proteins, including histone deacetylase inhibitors and DNA methylation inhibitors have been shown to reactivate the latent HTLV-1 provirus Immortalized, but untransformed cells display very similar epigenetic changes as those in transformed ATL cells, suggesting that epigenetic changes are likely an early event in leukemogenesis.

Aberrant activation of EZH2 protein coding enhancer of Zeste 2 polycomb repressive Complex 2 subunit , has been described in ATL, resulting in trimethylation of histone H3 lysine K 27, and suppression of a wide range of different genes. These findings suggest that the quarternary structure of the infected cell DNA may be a determinant of leukemogenesis. The current view of HTLV-1 transformation describes a multi-step process.

Initial steps of infection may occur in dendritic cells, which then present virus to mature T cells or their precursors, via cell-to-cell transmission of the virus Fig 3. The number of infected cells expands as a result of virus replication, and clonal amplification of infected cells.

Tax also promotes genetic instability, leading to genetic and epigenetic alterations within infected cells. Thus, infected cells evade these responses by down-modulating Tax expression. However, intermittent and transient expression of Tax by small numbers of cells within the infected cell population continue to drive T cell expansion and genetic damage. Thus, there is likely considerable genetic heterogeneity in the infected cell population.

There is selective expansion of infected cells that have undergone cellular alterations that promote cell proliferation, resistance to apoptosis, and evasion of the immune response. Subpopulations of infected cells with key genetic and epigenetic changes evolve into leukemia or lymphoma.

The prolonged period of evolution of the malignancy likely also contributes to therapy resistance, since effective anti-tumor treatments cooperate with active tumor immunity. The schematic hypothesizes that the initia HTLV-1 infected cell is a dendritic cell which presents infectious virus to a T cell. Subsequent expression of Tax, HBZ, and plus strand virus genes result in infection and clonal expansion of other T cells, resulting in genetic heterogeneity, as indicated by different colored cells.

Immune responses, as well as viral gene restrictions, result in little or no Tax and plus strand gene product expression from the majority of infected T cells, but a minor population of T cells with transient bursts of Tax expression.

Several decades of infection result in selection of cells with specific combinations of genetic and epigenetic alterations that result in adult T-cell leukemia lymphoma. Therapies that block HTLV-1 replication include nucleoside reverse transcriptase inhibitors e. Protease inhibitors and non-nucleoside reverse transcriptase inhibitors developed for HIV-1 have little activity against analogous proteins of HTLV Antivirals may impact viral load only during early stages of infection or during transient bursts of virus replication, but do not inhibit clonal expansion of previously infected cells.

Thus, their role in HTLV-1 infected individuals remains unclear. It is doubtful that this combination is functioning by inhibiting virus replication, but more likely has direct cytotoxic effects on the cells Zidovudine inhibits tolemerase and reactivation of p53 during cellular senescence Several therapeutic efforts have focused on Tax or Tax-induced gene products.

A therapeutic vaccine directed at Tax was tested in a clinical trial of ATLL, resulting in remission in two of three treated subjects Several inhibitors have been developed and tested in clinical trials. Studies of these agents against ATLL cell lines are reasonable. Direct inhibitors are currently being evaluated in other diseases in which IRF4 has been shown to be pathogenic, including multiple myeloma Lenalidomide binds to the E3 ubiquitin ligase, cereblon, and increases its activity This promotes ubiquitination and degradation of transcription factors Ikaros and Aiolos, and overcome their ability to promote IRF4 synthesis.

Currently, BET inhibitors are under investigation in other clinical settings Aberrant epigenetic changes in ATLL may also be therapeutically targeted. It is expected that these studies may provide an effective approach to this almost uniformly fatal malignancy, as well as approaches for prognostication and prevention of this disorder. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.

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Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. Semin Diagn Pathol. Author manuscript; available in PMC Mar 1. Lee Ratner.