In 1980, HumanT cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus to be discovered. HTLV-1 belongs to the Retroviridae family, the Orthoretrovirinae subfamily and ...to the deltaretrovirus genus. HTLV-1 preferentially infects CD4+ lymphoid cells in vivo. Three molecules have been identified for binding and/or entry of HTLV-1: heparan sulfate proteoglycans, neuropilin-1, and glucose transporter 1. An efficient transfer of the virus from an infected cell to a target cell can occur through the formation of a viral synapse and/or by virofilm structure. As for all retroviruses, HTLV-1 genome possesses three major ORFs (gag, pol and env) encoding the structural and enzymatic proteins. HTLV-1 encodes also some regulatory and auxillary proteins including the tax protein with transforming activities and the HBZ protein which plays a role in the proliferation and maintenance of the leukemic cells. HTLV-1 is present throughout the world with clusters of high endemicity including mainly Southern Japan, the Caribbean region, areas in South America and in intertropical Africa. The worldwide HTLV-1 infected population is estimated to be around 10–20 million. HTLV-1 has three modes of transmission: (1): mother to child, mainly linked to prolonged breast-feeding; (2): sexual, mainly occurring from male to female and (3): contaminated blood products. HTLV-1 possesses a remarkable genetic stability. HTLV-1 is the etiological agent of mainly two severe diseases: a malignant T CD4+ cell lymphoproliferation, of very poor prognosis, named Adult T cell Leukemia/Lymphoma (ATLL), and a chronic neuro-myelopathy named Tropical spastic paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). The lifetime risk among HTLV-1 carriers is estimated to be around 0.25 to 3%. TSP/HAM mainly occurs in adults, with a mean age at onset of 40-50 years and it is more common in women than in men. Blood transfusion is a major risk factor for TSP/HAM development. Clinically, TSP/HAM is mainly defined as a chronic spastic paraparesis and minor sensory signs. The onset is insidious with often gait disturbance and urinary symptoms. In more than 90% of the cases, the neurological features involve: spasticity and/or hyperreflexia of the lower extremities, urinary bladder disturbance, lower extremity muscle weakness, and in around 50% of the cases, sensory disturbances with low back pain. Central functions and cranial nerves are usually spared. The clinical course is generally progressive without remission. High levels of antibodies titers directed against HTLV-1 antigens are present in blood and cerebrospinal fluid (CSF). A high HTLV-1 proviral load is frequently observed in the blood. Mild to moderate increase of proteins may be present in the CSF. However, intrathecal production of specific HTLV-1 antibody index provides additional data to support the diagnosis. Brain white matter lesions on magnetic resonance imaging are frequent. A mild atrophy of the thoracic spinal cord can also be observed. Pathologically, it is characterized by a chronic inflammation with perivascular lymphocytic cuffing and mild parenchymal lymphocytic infiltrates. The cells are mostly CD4+ in early disease and mostly CD8+ in latter disease. Pyramidal tract damage with myelin and axonal loss, mainly in the lower thoracic spinal cord are observed. TSP/HAM pathogenesis is still poorly understood and viral and host factors as the proviral load and the cellular immune response play a major role in disease progression. TSP/HAM can be associated with other HTLV-1 associated symptoms (uveitis, myositis, infective dermatitis). Therapy of TSP/HAM remains disappointing and symptomatic treatment remains still the mainstay of therapy.
L’HumanT cell Leukemia/Lymphoma Virus Type 1 (HTLV-1) est le premier rétrovirus oncogène humain a avoir été isolé, en 1980. Il fait partie du genre deltaretrovirus. Alors que l’HTLV-1 infecte de nombreux types cellulaires in vitro, il infecte surtout les lymphocytes T CD4+ in vivo. La composition du complexe protéique permettant à HTLV-1 d’infecter une cellule est l’objet de débat. Trois types de molécules ont été identifiées : des héparanes sulfates protéoglycanes, la neuropiline 1 et le transporteur de glucose Glut-1. L’HTLV-1 se transmet principalement de cellule à cellule, à travers la formation d’une synapse virologique, mais aussi d’un biofilm viral sur la cellule donneuse. Outre les gènes gag, pro, pol et env communs à tous les rétrovirus, son génome comporte des phases ouvertes de lecture codant des protéines régulatrices et auxiliaires dont la protéine Tax (transformante) et la protéine HBZ qui participe à la prolifération des cellules leucémiques et au maintien du phénotype transformé. On estime que dix à 20 millions de personnes sont infectées dans le monde. Néanmoins, ce virus est surtout présent dans des foyers d’endémie (sud du Japon, région Caraïbe, certaines régions d’Amérique du Sud et d’Afrique intertropicale) où la séroprévalence virale, (1–2 % chez les adultes), peut atteindre parfois 20 à 40 %, en particulier chez les femmes âgées. L’HTLV-1 se transmet de la mère à l’enfant, surtout lors d’un allaitement prolongé, mais aussi sexuellement, surtout de l’homme vers la femme et lors de transfusions sanguines. La variabilité génétique de l’HTLV-1 est très faible. L’HTLV-1 est l’agent étiologique de deux maladies sévères : une prolifération maligne de lymphocytes CD4+ de très mauvais pronostic appelé Leucémie/Lymphome T de l’Adulte (ATLL) et une neuro-méylopathie chronique nommée Paraparésie Spastique Tropicale/Myélopathie associée à HTLV-1 (TSP/HAM). La TSP/HAM survient surtout chez l’adulte vers 40/50ans et plus fréquemment chez les femmes. Chez une personne infectée par l’HTLV-1, le risque de développer une TSP/HAM durant sa vie, varie entre 0,25 % et 3 %. La transfusion sanguine constitue un facteur de risque important de développer cette maladie. La TSP/HAM est une inflammation chronique médullaire thoracique avec une infiltration périvasculaire par des lymphocytes T, surtout CD4+ au début de la maladie mais CD8+ lors des phases tardives. L’apparition des symptômes est insidieuse, pouvant associer des troubles de la marche et des signes urinaires variés. Après quelques années d’évolution progressive sans rémission, les principaux signes neurologiques sont une spasticité et une faiblesse musculaire des membres inférieurs associées à des troubles urinaires et de fréquents signes sensitifs accompagnés de douleurs lombaires. La charge provirale est élevée dans les lymphocytes du sang et du LCR. Des titres élevés d’anticorps anti-HTLV-1 sont trouvés dans le plasma et le liquide céphalo-rachidien. La protéinorachie est modérée, cependant il existe une synthèse intratéchale d’anticorps spécifiques d’HTLV-1. La RMN montre parfois des lésions corticales, dont la spécificité est discutée, ainsi qu’une atrophie modérée de la moelle thoracique. Il existe des lésions du faisceau pyramidal avec une perte myélinique et axonale, surtout dans la moelle thoracique basse. La pathogenèse de la TSP/HAM reste mal connue mais elle associe probablement des facteurs viraux (charge provirale, expression des protéines virales Tax et HBZ) et de l’hôte (réponse immune T cytotoxique dirigée contre les épitopes viraux ou maladie auto-immune). La TSP/HAM est parfois associée à d’autres maladies liées à l’HTLV-1 (uvéite, myosite, dermatite infectieuse). La thérapeutique de la TSP/HAM est très décevante et reste principalement symptomatique.
Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). HTLV-1 ...infects 15 to 20
million people worldwide, while STLV-1 is endemic in a number of simian or ape species living in Africa or Asia. The high percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. STLV-3 viruses belong to the third PTLV type and are equally divergent from HTLV-1 than from HTLV-2. They are endemic in several monkey species that live in West, Central, and East Africa. In 2005, we and others reported the discovery of the human homolog (HTLV-3) of STLV-3 in two asymptomatic inhabitants from South Cameroon whose sera exhibited HTLV indeterminate serologies. More recently, we reported a third case of HTLV-3 infection in Cameroon suggesting that this virus is not rare in the human population living in Central Africa. Together with STLV-3, these three human viral strains belong therefore to the PTLV-3 type. A fourth HTLV type (HTLV-4) was also discovered in the same geographical area. Current studies are aimed at determining the prevalence, distribution and modes of transmission of these viruses as well as their possible association with human diseases. Furthermore, molecular characterization of their viral transactivator Tax is ongoing in order to look for possible oncogenic properties.
Les delta-rétrovirus humains (HTLV-1 et HTLV-2) et les virus simiens apparentés (STLV-1, STLV-2) appartiennent au groupe des rétrovirus lymphotropes de primate (PTLV). HTLV-1 infecte 15 à 20
millions de personnes, tandis que STLV-1 est endémique dans de nombreuses espèces de primates non humains de l’ancien monde. Du fait d’homologies de séquences très élevées entre les virus HTLV-1 et les virus STLV-1, il est clairement établi que la plupart des sous-types humains ont une origine simienne. Les virus simiens STLV-3 appartiennent au troisième type de PTLV et sont aussi divergents des PTLV-1 que des PTLV-2. Ils sont endémiques chez un grand nombre d’espèces de singes vivants en Afrique de l’Ouest, Centrale et de l’Est. En 2005, deux équipes dont la nôtre ont découvert l’existence du virus HTLV-3, homologue humain de STLV-3, chez deux habitants du sud Cameroun qui présentaient des sérologies HTLV indéterminées en western blot. Plus récemment, nous avons découvert un troisième cas d’infection par HTLV-3 au Cameroun. Ces résultats suggèrent que ces virus ne sont pas rares dans la population humaine en Afrique Centrale. Avec les STLV-3, ces virus humains forment donc le groupe des PTLV-3. Par ailleurs, un virus HTLV-4 a aussi été découvert dans la même région. Les travaux en cours visent à déterminer la prévalence, la distribution et les modes de transmission de ces virus et à rechercher une possible maladie associée. Par ailleurs, des études visent aussi à caractériser au niveau moléculaire leur protéine transactivatrice Tax à la recherche de son possible pouvoir oncogène.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of primary effusion lymphoma (PEL) and of Kaposi's sarcoma. PEL is an aggressive proliferation of B cells with poor prognosis. We ...evaluated both in vitro and in vivo the potential role of angiogenic factors secreted by PEL cells, that is, their interaction with endothelial cells and their implication in the invasive behavior of tumoral cells. In vitro, PEL-induced angiogenesis is dependent on vascular endothelial growth factor (VEGF) and VEGF receptors. However, although PEL cells produce VEGF and basic fibroblast growth factor (b-FGF) transcripts, they only secrete VEGF in vitro. In vivo, very high levels of both VEGF and b-FGF were found in the ascitic fluid of NOD/SCID mice injected with PEL cells. We then show evidence of cell adhesion and gap junction-mediated heterocellular communication between PEL cells and endothelial cells. Finally, we show that PEL cells extravasate through the endothelial barrier and that the specific tyrosine kinase inhibitor of VEGF receptors, PTK-787/ZK-222584, the anti-VEGF antibody, bevacizumab or the gap junction inhibitor 18-alpha-glycyrrhetinic acid, partially attenuate PEL cell extravasation. Angiogenesis, cell adhesion and communication likely contribute to the development of PEL and represent potential therapeutic targets.
Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. ...Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.
Human T-cell leukemia virus and simian T-cell leukemia virus (STLV) form the primate T-cell lymphotropic viruses group. Human T-cell leukemia virus type 1 and type 2 (HTLV-1 and HTLV-2) encode the ...Tax viral transactivator (Tax1 and Tax2, respectively). Tax1 possesses an oncogenic potential and is responsible for cell transformation both in vivo and in vitro. We and others have recently discovered the existence of human T-cell lymphotropic virus type 3. However, there is currently no evidence for the presence of a Tax protein in HTLV-3-infected individuals. We show that the serum of an HTLV-3 asymptomatic carrier and the sera of two STLV-3-infected monkeys contain specific anti-Tax3 antibodies. We also show that tax3 mRNA is present in the PBMCs obtained from an STLV-3-infected monkey, demonstrating that Tax3 is expressed in vivo. We further demonstrate that Tax3 intracellular localization is very similar to that of Tax1 and that Tax3 binds to both CBP and p300 coactivators. Using purified Tax3, we show that the protein increases transcription from a 4TxRE G-free cassette plasmid in an in vitro transcription assay. In all cell types tested, including transiently transfected lymphocytes, Tax3 activates its own promoter STLV-3 long terminal repeat (LTR), which contains only two Tax Responsive Elements (TREs), and activates also HTLV-1 and HTLV-2 LTRs. In addition, Tax3 also activates the NF-kappaB pathway. We also show that Tax3 possesses a PDZ-binding sequence at its C-terminal end. Our results demonstrate that Tax3 is a transactivator, and that its properties are more similar to that of Tax1, rather than of Tax2. This suggests the possible occurrence of lymphoproliferative disorders among HTLV-3-infected populations.
Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). The high ...percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. STLV-3 viruses belong to the third PTLV type and are equally divergent from both HTLV-1 and HTLV-2. They are endemic in several monkey species that live in West, Central and East Africa. In 2005, we, and others reported the discovery of the human homolog (HTLV-3) of STLV-3 in two asymptomatic inhabitants from South Cameroon whose sera exhibited HTLV indeterminate serologies. More recently, two other cases of HTLV-3 infection in persons living in Cameroon were reported suggesting that this virus is not extremely rare in the human population living in Central Africa. Together with STLV-3, these human viral strains belong to the PTLV-3 group. A fourth HTLV type (HTLV-4) was also discovered in the same geographical area. The overall PTLV-3 and PTLV-4 genomic organization is similar to that of HTLV-1 and HTLV-2 with the exception of their long terminal repeats (LTRs) that contain only two 21 bp repeats. As in HTLV-1, HTLV-3 Tax contains a PDZ binding motif while HTLV-4 does not. An antisense transcript was also described in HTLV-3 transfected cells. PTLV-3 molecular clones are now available and will allow scientists to study the viral cycle, the tropism and the possible pathogenicity in vivo. Current studies are also aimed at determining the prevalence, distribution, and modes of transmission of these viruses, as well as their possible association with human diseases. Here we will review the characteristics of these new simian and human retroviruses, whose discovery has opened new avenues of research in the retrovirology field.
To gain insight on the significance of human T-cell lymphotropic virus type 1 (HTLV-1) indeterminate serological reactivities, we studied villagers of South Cameroon, focusing on a frequent and ...specific HTLV-1 Gag indeterminate profile (HGIP) pattern (gag p19, p26, p28, and p30 without p24 or Env gp21 and gp46). Among the 102 sera studied, 29 from all age groups had a stable HGIP pattern over a period of 4 years. There was no epidemiological evidence for sexual or vertical transmission of HGIP. Seventy-five percent of HGIP sera reacted positively on MT2 HTLV-1-infected cells by immunofluorescence assay. However, we could not isolate any HTLV-1 virus or detect the presence of p19 Gag protein in cultures of peripheral blood mononuclear cells obtained from individuals with strong HGIP reactivity. PCR experiments conducted with primers for HTLV-1 and HTLV-2 (HTLV-1/2 primers) encompassing different regions of the virus did not yield HTLV-1/2 proviral sequences from individuals with HGIP. Using 11 peptides corresponding to HTLV-1 or HTLV-2 immunodominant B epitopes in an enzyme-linked immunosorbent assay, one epitope corresponding to the Gag p19 carboxyl terminus was identified in 75% of HGIP sera, while it was recognized by only 41% of confirmed HTLV-1-positive sera. A positive correlation between HTLV-1 optical density values and titers of antibody to Plasmodium falciparum was also demonstrated. Finally, passage of sera through a P. falciparum-infected erythrocyte-coupled column was shown to specifically abrogate HGIP reactivity but not the HTLV-1 pattern, suggesting the existence of cross-reactivity between HTLV-1 Gag proteins and malaria-derived antigens. These data suggest that in Central Africa, this frequent and specific Western blot is not caused by HTLV-1 infection but could instead be associated with P. falciparum infection.
HTLV-1 and innate immunity Journo, Chloé; Mahieux, Renaud
Viruses,
08/2011, Letnik:
3, Številka:
8
Journal Article, Book Review
Recenzirano
Odprti dostop
Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. ...Second, it primes development of the adaptive response, which completes the elimination of the pathogen or of infected cells. In vivo, HTLV-1 infects T lymphocytes that participate in adaptive immunity but also monocytes and dendritic cells that are major players in innate immunity. Herein, we will review the interplay between HTLV-1 and innate immunity. Particular emphasis is put on HTLV-1-induced alteration of type-I interferon (IFN-I) function. In vitro, the viral Tax protein plays a significant role in the alteration of IFN synthesis and signaling. Despite this, IFN-I/AZT treatment of Adult T-cell Leukemia/Lymphoma (ATLL) patients leads to complete remission. We will discuss a model in which exogenous IFN-I could act both on the microenvironment of the T-cells to protect them from infection, and also on infected cells when combined with other drugs that lead to Tax down-regulation/degradation.
Résumé: HTLV-1(virus humain de la leucémie/lymphome T de type 1) fut le premier rétrovirus humain à être associé à un cancer, la leucémie/lymphome T de l’adulte (ATLL). Cependant, HTLV-1 est un ...rétrovirus oncogène lent, et aucun site d’intégration préférentiel n’a pu être mis en évidence dans les cellules leucémiques. HTLV-1 est aussi l’agent étiologique d’une maladie neurologique chronique, la paraparésie spastique tropicale/myélopathie associée à HTLV-1 (TSP/HAM). Outre les gènes gag, pro, pol et env communs à tous les rétrovirus, son génome comporte des phases ouvertes de lecture codant des protéines régulatrices et auxiliaires dont la protéine Tax (transformante) et la protéine HBZ qui participe à la prolifération des cellules leucémiques et au maintien du phénotype transformé. Si les moyens de lutte contre l’ATLL ont fait des progrès importants avec des traitements antiviraux efficaces, notamment contre les formes chroniques et indolentes de la maladie, les thérapies permettant de soigner les malades atteints de TSP/HAM restent décevantes. Les résultats d’une étude récente qui associe inhibiteur d’histones déacétylase et substance antivirale sont discutés ici. Ce traitement permet une diminution très importante de la charge provirale (PVL) chez les porteurs asymptomatiques, alors que l’augmentation de celle-ci constitue généralement un marqueur pronostique défavorable de l’évolution vers la maladie.
Abstract: HTLV-1 was the first human oncogenic retrovirus to be discovered. It is the etiological agent of adult T leukemia/lymphoma (ATLL) and of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), two diseases that develop after a long latency period. Importantly, HTLV-1 does not cause ATLL through insertional mutagenesis. Apart from the gag, pro, pol and env genes, which are common to all retroviruses, HTLV-1 genome also encodes regulatory and auxiliary viral proteins. Among the former, Tax promotes cell transformation and HBZ is involved in the leukemic cells proliferation and in the maintenance of the transformed phenotype. Anti-ATLL therapies have lately made significant progress with an efficient antiviral treatment against the chronic and smoldering forms of this leukemia, but an efficient treatment of TSP/HAM patients is still lacking. Results from a recent study associating histone acetylase inhibitor with an anti-viral drug will be discussed here. While an increase in proviral load is considered a marker for disease progression, this treatment allows a significant drop of the proviral load in asymptomatic carriers.
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