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Human T cell leukemia virus type 1 (HTLV-1) was the first discovered human retrovirus and the etiologic agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Shortly after the discovery of HTLV-1, human T-cell leukemia virus type 2 (HTLV-2) was isolated from a patient with hairy cell leukemia. Despite possession of similar structural features to HTLV-1, HTLV-2 has not been definitively associated with lymphoproliferative disease. Since their discovery, studies have been performed with the goal of highlighting the differences between HTLV-1 and HTLV-2. A better understanding of these differences will shed light on the specific pathogenic mechanisms of HTLV-1 and lead to novel therapeutic targets. This review will compare and contrast the two oldest human retroviruses with regards to epidemiology, genomic structure, gene products, and pathobiology.

Frequent onset before 10 years of age Marked female predominance Related to vertical transmission of HTLV-1 Very frequent association with IDH Presence of rapid progressive courses Occurrence of infected cells in the CSF Abstract Background Human T-cell lymphotropic virus type-1 (HTLV-1) may cause severe diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). The clinical characteristics and progression of 25 early onset HAM/TSP associated or not to IDH were described. Methods Following-up 37 IDH patients with neurological examinations, 54% developed HAM/TSP. To these cases were added 5 cases of juvenile HAM/TSP. The patients were HTLV-1+ and were submitted to dermatological and neurological examinations. Diagnosis of HAM/TSP was performed according to Osame et al (1990) and Castro-Costa et al (2006) criteria. Results Twenty-one patients were classified as definite HAM/TSP by both criteria, 3 as probable HAM/TSP by Osame et al, and another as probable HAM/TSP according to Castro-Costa et al Median age at onset of neurological manifestations was 9 years for the IDH/HAM/TSP group and 16 years for the HAM/TSP group (P = .045). In 12 patients, the onset of neurological manifestations occurred when they were less than 10 years of age. In the group IDH/HAM/TSP, the neurological symptoms always begun during the period of activity of IDH. The progression of HAM/TSP evaluated in 17 cases was heterogeneous, and 3 had rapid progressive course. Conclusions The juvenile HAM/TSP may occur very early and also presents marked female predominance. Progression of IDH to HAM/TSP before 19 years of age is frequent (54%). Rapid progressive form may also occur in early HAM/TSP. As juvenile IDH and HAM/TSP are due to vertical transmission through breastfeeding, it is very important to avoid this pathway of infection.

Human T-cell leukemia virus type 1 (HTLV-1) causes serious and intractable diseases in some carriers after infection. The elimination of infected cells is considered important to prevent this onset, but there are currently no means by which to accomplish this. We previously developed “virotherapy”, a therapeutic method that targets and kills HTLV-1-infected cells using a cytolytic recombinant vesicular stomatitis virus (rVSV). Infection with rVSV expressing an HTLV-1 primary receptor elicits therapeutic effects on HTLV-1-infected envelope protein (Env)-expressing cells in vitro and in vivo. Simian T-cell leukemia virus type 1 (STLV-1) is closely related genetically to HTLV-1, and STLV-1-infected Japanese macaques (JMs) are considered a useful HTLV-1 surrogate, non-human primate model in vivo. Here, we performed an in vitro drug evaluation of rVSVs against STLV-1 as a preclinical study. We generated novel rVSVs encoding the STLV-1 primary receptor, simian glucose transporter 1 (JM GLUT1), with or without an AcGFP reporter gene. Our data demonstrate that these rVSVs specifically and efficiently infected/eliminated the STLV-1 Env-expressing cells in vitro. These results indicate that rVSVs carrying the STLV-1 receptor could be an excellent candidate for unique anti-STLV-1 virotherapy; therefore, such antivirals can now be applied to STLV-1-infected JMs to determine their therapeutic usefulness in vivo.

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive and refractory hematologic malignancy that is caused by human T‐cell leukemia virus type‐1 (HTLV‐1) retrovirus. ATL results from a combination of viral latency and the accumulation of abnormalities throughout the genome, epigenome, transcriptome, and signaling pathways. Despite numerous studies, the data have been largely fragmentary, and a comprehensive understanding of this disease remains unclear. Recent comprehensive analyses have contributed not only to the identification of fundamental molecular abnormalities in ATL, but also to the development of novel therapeutic strategies and prognostic models. In this review, an overview of the latest advances in the genomic, epigenomic, and transcriptomic alterations associated with ATL is provided, which highlights the opportunities for clinical management of ATL. Integrated omics approaches will further increase our understanding of refractory disease and provide a foundation for designing new treatments that target core molecular drivers.

The human T cell leukemia virus type 1 (HTVL-1), first reported in 1980 by Robert Gallo’s group, is the etiologic agent of both cancer and inflammatory diseases. Despite approximately 40 years of investigation, the prognosis for afflicted patients remains poor with no effective treatments. The virus persists in the infected host by evading the host immune response and inducing proliferation of infected CD4 + T-cells. Here, we will review the role that viral orf - I protein products play in altering intracellular signaling, protein expression and cell–cell communication in order to escape immune recognition and promote T-cell proliferation. We will also review studies of orf - I mutations found in infected patients and their potential impact on viral load, transmission and persistence. Finally, we will compare the orf - I gene in HTLV-1 subtypes as well as related STLV-1.

Human T cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. The HTLV-1 bZIP factor (HBZ) gene is constantly expressed in HTLV-1 infected cells and ATL cells. HBZ protein suppresses transcription of the tax gene through blocking the LTR recruitment of not only ATF/CREB factors but also CBP/p300. HBZ promotes transcription of Foxp3, CCR4, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). Thus, HBZ is critical for the immunophenotype of infected cells and ATL cells. HBZ also functions in its RNA form. HBZ RNA suppresses apoptosis and promotes proliferation of T cells. Since HBZ RNA is not recognized by cytotoxic T cells, HTLV-1 has a clever strategy for avoiding immune detection. HBZ plays central roles in maintaining infected T cells in vivo and determining their immunophenotype.

Adult T-Cell Leukemia/Lymphoma (ATLL) is a malignancy that arises from T-cells infected with the human T-cell lymphotropic virus type 1 (HTLV-1). The disease is characterized by uncontrolled proliferation and reduced apoptosis of malignant T cells, which contributes to tumor progression and resistance to therapy. Anoikis is a specific form of programmed cell death triggered by the loss of cell–matrix or cell–cell adhesion, playing a critical role in preventing detached cells from surviving and forming tumors. Dysregulation of anoikis has been implicated in cancer metastasis and therapeutic resistance across various malignancies; however, its role in ATLL remains largely unexplored. To our knowledge, this is the first study to investigate anoikis-related genes in ATLL subtypes, particularly across its major subtypes: acute, chronic, and smoldering. In this study, we explored anoikis-related differentially expressed genes to identify those specifically associated with each subtype. We then applied Least Absolute Shrinkage and Selection Operator (LASSO) regression to select the most informative features. Subsequently, we employed decision trees, random forest, extreme gradient boosting, support vector machine, and logistic regression algorithms to identify classifier genes distinguishing each ATLL subtype from asymptomatic carriers. The identified biomarkers include SMARCE1 and CASP3 for acute, TGFΒ1 and MTA1 for chronic, and CXCL1 and LGALS8 for smoldering subtypes. These genes are involved in cell adhesion, survival signaling, and apoptosis—key processes in cellular homeostasis and oncogenesis. Our findings provide novel insights into the molecular mechanisms linking anoikis to ATLL subtypes and highlight potential therapeutic targets.

Human T cell leukemia virus (HTLV-1) is an oncoretrovirus that infects at least 10 million people worldwide. HTLV-1 exhibits a remarkable genetic stability, however, viral strains have been classified in several genotypes and subgroups, which often mirror the geographic origin of the viral strain. The Cosmopolitan genotype HTLV-1a, can be subdivided into geographically related subgroups, e.g. Transcontinental (a-TC), Japanese (a-Jpn), West-African (a-WA), North-African (a-NA), and Senegalese (a-Sen). Within each subgroup, the genetic diversity is low. Genotype HTLV-1b is found in Central Africa; it is the major genotype in Gabon, Cameroon and Democratic Republic of Congo. While strains from the HTLV-1d genotype represent only a few percent of the strains present in Central African countries, genotypes -e, -f, and -g have been only reported sporadically in particular in Cameroon Gabon, and Central African Republic. HTLV-1c genotype, which is found exclusively in Australo-Melanesia, is the most divergent genotype. This reflects an ancient speciation, with a long period of isolation of the infected populations in the different islands of this region (Australia, Papua New Guinea, Solomon Islands and Vanuatu archipelago). Until now, no viral genotype or subgroup is associated with a specific HTLV-1-associated disease. HTLV-1 originates from a simian reservoir (STLV-1); it derives from interspecies zoonotic transmission from non-human primates to humans (ancient or recent). In this review, we describe the genetic diversity of HTLV-1, and analyze the molecular mechanisms that are at play in HTLV-1 evolution. Similar to other retroviruses, HTLV-1 evolves either through accumulation of point mutations or recombination. Molecular studies point to a fairly low evolution rate of HTLV-1 (between 5.6E−7 and 1.5E−6 substitutions/site/year), supposedly because the virus persists within the host via clonal expansion (instead of new infectious cycles that use reverse transcriptase).

Adult T-cell leukemia/lymphoma develops decades after Human T-lymphotropic virus type 1 (HTLV-1) infection. Factors like proviral load (PVL), soluble interleukin-2 receptors (sIL-2R), and clonality are associated with its pathogenesis. However, a comprehensive assessment using multiple factors of ATL development and progression based on flow cytometry (HAS-Flow) has not been performed. We conducted a 10-year clinical follow-up of 160 asymptomatic people living with HTLV-1 using HAS-Flow, PVL, sIL-2R, and the HTLV-1 integration site identification. The cases were classified into three groups based on cell adhesion molecule 1 (CADM1)-expressing cells by HAS-Flow: Group 1 (≤ 10%, 115 cases), Group 2 (> 10% to ≤ 25%, 33 cases), and Group 3 (> 25%, 12 cases). In the follow-up, no cases in Group 1 developed ATL, while five cases in Group 2 and nine in Group 3 did. Among the developed ATL, one case in Group 2 and six in Group 3 progressed to aggressive ATL. Higher CADM1-expressing cells and sIL-2R levels were linked to earlier ATL development. The HTLV-1 integration site was identified in all aggressive ATL cases. Thus, evaluating CADM1-expressing cells by HAS-Flow, assessing sIL-2R, and identifying the HTLV-1 integration site can better predict ATL development and progression to aggressive ATL.

Proviral load (PVL) is one of the determining factors for the pathogenesis and clinical progression of the human T-lymphotropic virus type I (HTLV-1) infection. In the present study, we optimized a sensitive multiplex real-time PCR for the simultaneous detection and quantification of HTLV-1 proviral load and beta-globin gene as endogenous control. The values obtained for HTLV-1 PVL were used to monitor the clinical evolution in HTLV-1-infected individuals. A vector containing cloned DNA targets of the real-time PCR for the beta-globin gene and the HTLV-1 pol region was constructed. For the reaction validation, we compared the amplification efficiency of the constructed vector and MT-2 cell line containing HTLV-1. The analytical sensitivity of the reaction was evaluated by the application of a standard curve with a high order of magnitude. PVL assay was evaluated on DNA samples of HTLV-1 seropositive individuals. The construct showed adequate amplification for the beta-globin and HTLV-1 pol genes when evaluated as multiplex real-time PCR (slope = 3.23/3.26, Y -intercept = 40.18/40.73, correlation coefficient r 2 = 0.99/0.99, and efficiency = 103.98/102.78, respectively). The quantification of PVL using the MT-2 cell line was equivalent to the data obtained using the plasmidial curve (2.5 copies per cell). In HTLV-1-associatedmyelopathy/tropical spastic paraparesis patients, PVL was significantly higher (21315 ± 2154 copies/10 5 PBMC) compared to asymptomatic individuals (1253 ± 691 copies/10 5 PBMC). The obtained results indicate that the optimized HTLV-1 PVL assay using plasmidial curve can be applied for monitoring and follow-up of the progression of HTLV-1 disease. The use of a unique reference plasmid for both HTLV-1 and endogenous gene allows a robust and effective quantification of HTLV-1 PVL. In addition, the developed multiplex real-time PCR assay was efficient to be used as a tool to monitor HTLV-1-infected individuals.