T-lymphotropic virus type 1

Another possible mechanism that could cause epigenetic silencing has been elucidated recently by Fan et al. The authors have attributed the nonsense mutations in the plus strand of the proviral DNA coding for env, tax, p13 and p30 to be responsible for the reduced viral gene expression in these cells.

The generation of nonsense mutations does not affect the Hbz gene, which codes from the minus strand. Moreover, there are very few mutation sites in the opposite strand of the HBZ coding region.

Therefore, the functional activity of HBZ is not affected. It also was shown that these mutations occur both in ATL cells and HTLV-1 infected cells from asymptomatic carriers, indicating that these mutations do not occur during oncogenesis but are present even during the carrier state. The mutations were present in the leukemic cells and not in the non-leukemic HTLV-1 infected cells, suggesting that there is a selection for these cells during leukemogenesis, which likely favors the virus by promoting immune evasion [ ].

This deletion was detected in 3. In all these cases, the coding sequences of the Hbz gene were intact [ ]. Taken together, the possible mechanism of HTLVinduced oncogenesis suggests that Tax is expressed initially to induce transformation and cell proliferation. Tax-specific CTLs mediate the death of virus infected cells. Thus, the virus is forced to down-regulate Tax expression to below detectable levels by the expression of HBZ in order to persist in the host.

Since HBZ-specific CTLs do not lyse ATL cells and HBZ can promote and maintain the leukemic state of these cells, this mechanism ought to be favored by the virus in order to evade immune surveillance and continue to persist in the host. However, why it would be in the best interest of the virus to cause cancer, which is a dead end situation for itself, although in a very small percentage of infected individuals, is still an unanswered question.

HTLVs are complex retroviruses with unique proteins that have oncogenic potential. HTLV-2 is not etiologically oncogenic and has been associated with some neurological disorders.

A complete understanding of the functions of the viral genes would give insights into the pathogenic mechanisms by which HTLV-1 induces oncogenesis. In this review we summarize the data published so far in this field with pertinent comparisons to HTLV-2, the non-leukemic counterpart. Like simple retroviruses, HTLV-1 expresses structural and enzymatic proteins for its assembly and maturation, and for entry into new target cells.

HTLV-1 also expresses regulatory and accessory proteins that are essential for viral persistence, immune evasion and ultimately, leukemogenesis. Although, the exact mechanisms and pathways have not been fully elucidated, much is known thus far. For instance, Tax is expressed in the early stages of infection to establish viral transcription and induce T cell transformation by regulating cellular transcription factors, inducing G1 to S phase transition and DNA damage resulting in genetic instability, and promoting proliferation of genetically altered leukemic cells.

Subsequently, HBZ suppresses Tax expression to evade immune elimination by Tax-specific CTLs, and also complements for Tax to support proliferation; it provides a second oncogenic signal required for the maintenance of the leukemic cell.

Further investigations are warranted to determine the additional events in the minor population that progresses to ATL. National Center for Biotechnology Information , U. Journal List Viruses v.

Published online Sep Priya Kannian 1, 2 and Patrick L. Patrick L. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Human T lymphotropic viruses HTLVs are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo.

General Background and Overview Human T lymphotropic virus type 1 HTLV-1 is a complex leukemogenic retrovirus with a single stranded positive sense RNA genome that expresses unique proteins with oncogenic potential. Open in a separate window. Figure 1. Viral transmission Of the many possible routes of virus transmission, mother-to-child through breast feeding is the most predominant mode [ 81 ].

Viral pathogenesis The pathogenesis of ATL involves four stages: infection, polyclonal proliferation, clinical latency and tumorigenesis. Role of Tax in HTLV-1 induced oncogenesis Tax, a transactivator protein, triggers a plethora of events like cell signaling, cell cycle regulation and interference with checkpoint control and inhibition of DNA repair. Tax and T cell transformation Apart from activating viral gene transcription, Tax induces various cellular functions in the HTLV-1 infected cells and thus, renders them susceptible to viral persistence and thereby initiates neoplastic transformation.

Table 1. Structural and functional differences between the unspliced and spliced Hbz. Yes mRNA transcription efficiency [ 47 , , ] 0. Figure 2. Conclusions HTLVs are complex retroviruses with unique proteins that have oncogenic potential. References and Notes 1. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.

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Human T-lymphotropic virus type 1 mitochondrion-localizing protein p13II sensitizes Jurkat T cells to Ras-mediated apoptosis. Oncoviral bovine leukemia virus G4 and human T-cell leukemia virus type 1 p13 II accessory proteins interact with farnesyl pyrophosphate synthetase.

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Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Karin M. Nuclear factor-kappaB in cancer development and progression. Higuchi M, Fujii M. Human T-cell leukemia virus type I Tax induces expression of the rel-related family of kappa B enhancer-binding proteins: Evidence for a pretranslational component of regulation. Sun SC, Yamaoka S. Wu X, Sun SC. EMBO Rep. Phosphorylation of the human T-cell leukemia virus type 1 transactivator Tax on adjacent serine residues is critical for Tax activation.

Ubiquitination of human T-cell leukemia virus type 1 tax modulates its activity. Exclusive ubiquitination and sumoylation on overlapping lysine residues mediate NF-kappaB activation by the human T-cell leukemia virus tax oncoprotein.

Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kappaB activation. The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation. Acetylation of the human T-cell leukemia virus type 1 Tax oncoprotein by p promotes activation of the NF-kappaB pathway. PLoS Pathog. EMBO J. Activation of the interleukin-2 receptor alpha gene: regulatory role for DNA-protein interactions flanking the kappa B enhancer.

New Biol. Interleukin overexpression by tax transactivation: a potential autocrine stimulus in human T-cell leukemia virus-infected lymphocytes. Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site. HTLV-1 belongs to the complex retroviruses family. These proteins not only control viral gene transcription, but also modulate the proliferation of infected cells. Indeed, the fact that HTLV-1 induces the proliferation of infected cells facilitates its transmission through cell-to-cell contact rather than through the release of viral particles see also Section 1 and Fig.

The open reading frame I of the pX region of HTLV-1 encodes the protein p12, which is located in the endoplasmic reticulum and the Golgi. In quiescent primary lymphocytes and in vivo , p12 is important for establishing HTLV-1 infection and optimal viral infectivity.

The p12 protein therefore facilitates host-cell activation, and the establishment of persistent infection Collins et al. The protein p13 contains a mitochondrial-targeting signal, and exists in the nucleus and mitochondria. Mutation of the p13 gene impairs viral proliferation in vivo , indicating that p13 is critical for viral replication Hiraragi et al. In addition, p13 expression is associated with a suppressed cell proliferation in vitro Silic-Benussi et al.

The protein p30 is a nuclear and nucleolar protein Koralnik et al. Therefore, p30 is a post-transcriptional negative regulator of viral replication and viral gene expression Nicot et al. Tax, a kD phosphoprotein, encoded from a spliced mRNA, is found mainly in the nucleus but also in the cytoplasm Meertens et al. Tax interacts with several host factors Boxus et al. The transduction of a pX-containing sequence into primary human T Lymphocytes by use of a defective simian herpesvirus is sufficient to immortalize these cells Grassmann et al.

However, since this vector could express not only tax but also the genes p12, p13, p30 and HBZ , it was difficult to conclude whether Tax was the only responsible viral protein for cell transformation.

Subsequently, immortalization ILdependent growth of human CD4-positive T cells was demonstrated in vitro by the use of a retroviral vector expressing only the tax gene Akagi et al. In addition, the transforming ability of Tax was demonstrated in the Rat-1 fibroblast cell line in vitro in a soft-agar assay, and in vivo in nude mice Tanaka et al.

These findings clearly showed that Tax is oncogenic. In addition, several studies with animals transgenic for Tax have clearly demonstrated that Tax expression leads to the induction of tumours, confirming that Tax is oncogenic in vivo see Section 4. The transcription factor p53 is a crucial element in the cellular defence against tumour development.

Tax activates the transcription of viral genes through three imperfect 21 base-pair repeat elements, the Tax-responsive element TRE Fujisawa et al. Tax can interact with transcriptional co-activators, CREB-binding protein CBP and p, that acetylate histones in the promoter region. Therefore, HBZ gene transcription is relatively constant, and is correlated with proviral load Usui et al.

Among all the viral proteins, only Tax has the ability to immortalize CD4-positive T cells in vitro see above. This is therefore indicative of chromosomal instability in ATLL cells where the altered functions of several centrosome-associated proteins seem also to be involved in the Tax-driven aneuploidy Afonso et al. It is tempting to speculate that the loss of HsMAD1 function could be linked to the loss or modification of the centrosomal activity Jin et al. This interaction leads to a premature mitotic exit, and may contribute to aneuploidy Liu et al.

By the use of in-situ fluorescence microscopy the authors demonstrated that Tax binds to and co-localizes with endogenous TAX1BP2, forming peri-nuclear dots. In the absence of Tax, overexpression of TAX1BP2 leads to a reduction in the number of cells that contain supernumerary centrosomes.

In addition, during mitosis, Tax binds to Ran and RanBP1, which fragments spindle poles, and induces multipolar segregation Peloponese et al. After infection followed by a couple of cycles during which HTLV-1 uses its reverse transcriptase, the virus is amplified via clonal proliferation of the infected cells Takemoto et al. The same infected clones survive in vivo , indicating that clonal proliferation is persistent Etoh et al.

A prospective study has shown that this clonal proliferation is associated with the onset of ATLL in some cases Okayama et al. Of note, the proviral load ranges from less than 0. It is likely that a high proviral load is associated with a higher risk of developing ATLL Tachibana et al.

Viral gene expression differs between in-vitro-transformed cell lines and primary ATLL cells in a manner that is similar to the relation between EBV-transformed cells and Burkitt lymphoma cells.

As an example, the cumulative lifetime risk of developing ATLL was estimated to be 6. ATLL cells retain the HTLV-1 provirus in the genome, but as stated above, defective proviruses are frequently detected, which are classified into two types.

It is frequently observed in acute and lymphoma-type ATLLs whereas it is quite rare in chronic ATLL, indicating that this defective provirus is likely to be associated with disease progression Tamiya et al. Detailed analyses show that the type-2 defective provirus can be generated before and after integration.

The frequency of type-2 defective proviruses is low in carriers, indicating that these defective proviruses were selected during leukaemogenesis. Another possibility is that infected cells with the type-2 defective provirus tend to transform into ATLL cells. ATLL cells with the type-2 defective provirus frequently cannot produce Tax as a result of the deletion of the promoter or the deletion of the second exon. However, all cases with the type-2 defective provirus maintain an intact HBZ gene sequence Miyazaki et al.

As a mechanism of retroviral oncogenesis, the integrated LTR activates the transcription of cellular oncogenes, flanking integration sites. Several ways by which tumour-suppressor genes can be inactivated have been demonstrated in cancer cells.

Deletion or mutation of the p16 INK4A gene has also been reported. Cytogenetic analysis of ATLL cells showed a common breakpoint cluster region in chromosome 10p Further analyses have shown that the transcription factor 8 TCF8 is frequently disrupted by several mechanisms, including epigenetic silencing. There have been a few reports of cellular oncogenes in ATLL cells. Expression of Tgat in NIH3T3 cells resulted in cell transformation, indicated by anchorage-independent growth in semisolid medium, and tumorigenicity in nude mice Yoshizuka et al.

The frequency of opportunistic infections is fairly high among ATLL patients, indicating that T-cell-mediated immunity is severely impaired in such patients. The presence of the parasite S. In a study in the Japanese districts of Kyushu and Okinawa, where strongyloidiasis is endemic, 36 patients were identified as seropositive for HTLV It has been suggested that the parasitic infestation with S.

Animals, including rabbits, rats, and monkeys can be experimentally infected with HTLV-1 Lairmore et al.

In rabbits and rats, HTLV-1 infection is persistent, and induces host immune response. However, HTLV-1 does not lead to definite diseases in these two species.

Sciureus led to a substantial decrease in the proliferation rate of the CD4-positive T-cell population in those infected animals that were affected by a pathology similar to ATLL in humans Debacq et al.

Co-infection of rhesus macaques Macaca mulatta with HTLV-1 and simian immunodeficiency virus 1 SIV-1 increased the number of multilobulated lymphocytes in the circulation. So far, non-human primates represent the only suitable animal model to study human ATLL. Several transgenic animal models have been established to study HTLV-1; the Tax protein has been shown to be oncogenic in several of these models.

The type of tumour depends on the promoter used in each study: transgenic mice expressing Tax using the granzyme B promoter developed tumours of natural killer cells Grossman et al. HBZ -transgenic mice have also been shown to display increased T-cell proliferation Satou et al. The host immune system influences the condition of viral infection, and the diseases induced by it. Large interindividual variations in proviral load are commonly observed between HTLV-1 carriers, but the amount of provirus is relatively constant in HTLVinfected individuals over time Kwaan et al.

This was associated with viral gene expression, and indicates that active proliferation induced by viral infection induces the host immune response, and that the proviral load is determined by a balance between Cytotoxic T Lymphocytes activity and viral gene expression.

There is strong mechanistic evidence supporting the role of HTLV-1 in human carcinogenesis. The viral protein Tax has the ability to immortalize and to transform human T cells. At the leukaemic stage, the expression of Tax is often not maintained, but the viral protein HBZ continues to be expressed, and supports the sustained growth of the leukaemic cells see Figure 4.

There is sufficient evidence in humans for the carcinogenicity of HTLV Turn recording back on. National Center for Biotechnology Information , U. Search term. Exposure Data 1. Taxonomy, structure, and biology 1. Taxonomy Retroviruses can be classified according to the morphology of their virion core or according to sequence homologies that become evident after phylogenetic analyses.

Structure of the virion The structure of retroviruses is reviewed in the Monograph on HIV-1 in this volume. Structure of the viral genome As stated above, HTLV-1 is a complex retrovirus that contains regulatory genes tax and rex and accessory genes p12, p13, p30 and HBZ , in addition to structural genes gag, pol and env see Fig.

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