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The Brazilian Journal of Infectious... 2021Infection by human T-cell lymphotropic virus type 1 (HTLV-1) occurs in lymphocytes, which travel throughout the body, thus affecting several target organs and causing... (Review)
Review
Infection by human T-cell lymphotropic virus type 1 (HTLV-1) occurs in lymphocytes, which travel throughout the body, thus affecting several target organs and causing varied clinical outcomes, particularly in populations that are underserved and do not have access to healthcare. However, the mechanism of pathogenesis is not yet fully understood. The TAX and HTLV-1 basic leucine zipper factor (HBZ) proteins maintain viral persistence and affect pathogenesis through cell proliferation and immune and inflammatory responses that accompany each clinical manifestation. TAX expression leads to inhibition of transcription error control, OX40 overexpression, and cell proliferation in adult T-cell leukemia (ATL). OX40 levels are elevated in the central nervous system (CNS), and the expression of TAX in the CNS causes neuronal damage and loss of immune reactivity among patients with HTLV-1-associated myelopathy (HAM). HBZ reduces viral replication and suppresses the immune response. Its cell compartmentalization has been associated with the pathogenesis of HAM (cytoplasmic localization) and ATL (nuclear localization). TAX and HBZ seem to act antagonistically in immune responses, affecting the pathogenesis of HTLV-1 infection. The progression from HTLV-1 infection to disease is a consequence of HTLV-1 replication in CD4 T and CD8 T lymphocytes and the imbalance between proinflammatory and anti-inflammatory cytokines. The compartmentalization of HBZ suggests that this protein may be an additional tool for assessing immune and inflammatory responses, in addition to those already recognized as potential biomarkers associated with progression from infection to disease (including human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), interleukin (IL)-6, IL-10, IL-28, Fas, Fas ligand, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and mannose-binding lectin).
Topics: Basic-Leucine Zipper Transcription Factors; Biomarkers; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Retroviridae Proteins
PubMed: 34256025
DOI: 10.1016/j.bjid.2021.101594 -
Viruses Sep 2020(HTLV-1) and (BLV) belong to the genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a... (Review)
Review
(HTLV-1) and (BLV) belong to the genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). BLV causes neoplastic proliferation of B cells in cattle: enzootic bovine leucosis (EBL). Despite the severity of these conditions, infection by HTLV-1 and BLV appear in most cases clinically asymptomatic. These viruses can undergo latency in their hosts. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infection, as well as for pathogenesis in vivo. In this review, we will present the mechanisms that control proviral activation and retroviral latency in deltaretroviruses, in comparison with other exogenous retroviruses. The 5' long terminal repeats (5'-LTRs) play a main role in controlling viral gene expression. While the regulation of transcription initiation is a major mechanism of silencing, we discuss topics that include (i) the epigenetic control of the provirus, (ii) the -elements present in the LTR, (iii) enhancers with cell-type specific regulatory functions, (iv) the role of virally-encoded transactivator proteins, (v) the role of repressors in transcription and silencing, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs. Finally, we discuss how a better understanding of these mechanisms may allow for the development of more effective treatments against .
Topics: Animals; Enhancer Elements, Genetic; Epigenesis, Genetic; Gene Expression Regulation, Viral; Human T-lymphotropic virus 1; Humans; Leukemia Virus, Bovine; Mutation; RNA, Untranslated; Terminal Repeat Sequences; Viral Proteins; Virus Latency
PubMed: 32992917
DOI: 10.3390/v12101079 -
PLoS Pathogens Feb 2023The complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1), primarily infects CD4+ T-cells in vivo. Infectious spread within this cell population requires...
The complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1), primarily infects CD4+ T-cells in vivo. Infectious spread within this cell population requires direct contact between virally-infected and target cells. The HTLV-1 accessory protein, HBZ, was recently shown to enhance HTLV-1 infection by activating intracellular adhesion molecule 1 (ICAM-1) expression, which promotes binding of infected cells to target cells and facilitates formation of a virological synapse. In this study we show that HBZ additionally enhances HTLV-1 infection by activating expression of myoferlin (MyoF), which functions in membrane fusion and repair and vesicle transport. Results from ChIP assays and quantitative reverse transcriptase PCR indicate that HBZ forms a complex with c-Jun or JunB at two enhancer sites within the MYOF gene and activates transcription through recruitment of the coactivator p300/CBP. In HTLV-1-infected T-cells, specific inhibition of MyoF using the drug, WJ460, or shRNA-mediated knockdown of MyoF reduced infection efficiency. This effect was associated with a decrease in cell adhesion and an intracellular reduction in the abundance of HTLV-1 envelope (Env) surface unit (SU) and transmembrane domain (TM). Lysosomal protease inhibitors partially restored SU levels in WJ460-treated cells, and SU localization to LAMP-2 sites was increased by MyoF knockdown, suggesting that MyoF restricts SU trafficking to lysosomes for degradation. Consistent with these effects, less SU was associated with cell-free virus particles. Together, these data suggest that MyoF contributes to HTLV-1 infection through modulation of Env trafficking and cell adhesion.
Topics: Humans; Basic-Leucine Zipper Transcription Factors; CD4-Positive T-Lymphocytes; Human T-lymphotropic virus 1; Retroviridae Proteins
PubMed: 36827461
DOI: 10.1371/journal.ppat.1011202 -
Therapeutic approaches for HTLV-1-associated adult T-cell leukemia/lymphoma: a comprehensive review.Medical Oncology (Northwood, London,... Sep 2023Adult T-cell leukemia/lymphoma (ATLL), an infrequent malignancy resultant from human T-cell lymphotropic virus type I (HTLV-1), exhibits a spectrum of phenotypes,... (Review)
Review
Adult T-cell leukemia/lymphoma (ATLL), an infrequent malignancy resultant from human T-cell lymphotropic virus type I (HTLV-1), exhibits a spectrum of phenotypes, encompassing acute, smoldering, lymphomatous, and chronic variants, each bearing distinct clinical presentations. The preponderant acute manifestation is characterized by hypercalcemia, systemic manifestations, organomegaly, and dermatological eruptions. Conversely, the chronic phenotype is typified by lymphocytosis and/or cutaneous eruptions, while smoldering ATLL assumes an asymptomatic course. Immunocompromise afflicts ATLL patients, heightening their vulnerability to opportunistic infections that frequently intricately intertwine with disease progression. Therefore, an early diagnosis is crucial to manage the disease appropriately. While conventional chemotherapeutic regimens have shown limited success, especially in acute and lymphoma types, recent studies suggest that allogeneic stem cell transplantation might enhance treatment results because it has shown promising outcomes in some patients. Novel therapeutics, such as interferon and monoclonal antibodies, have also shown promise, but more research is needed to confirm their efficacy. Moreover, the identification of biomarkers for ATLL and genetic changes in HTLV-1 infected cells has led to the development of targeted therapies that have shown remarkable success in clinical trials. These targeted therapies have the potential to offer a more personalized approach to the treatment of ATLL. The aim of our review is to elaborate on conventional and novel therapies and the efficiency of mentioned treatments.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Antibodies, Monoclonal; Disease Progression; Hematopoietic Stem Cell Transplantation
PubMed: 37689806
DOI: 10.1007/s12032-023-02166-8 -
The Lancet. Microbe Mar 2022
Topics: HTLV-I Infections; Health Inequities; Human T-lymphotropic virus 1; Humans
PubMed: 35544072
DOI: 10.1016/S2666-5247(21)00330-X -
Viruses Feb 2016Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and chronic inflammatory diseases. HTLV-1 bZIP factor (HBZ) is transcribed as an antisense... (Review)
Review
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and chronic inflammatory diseases. HTLV-1 bZIP factor (HBZ) is transcribed as an antisense transcript of the HTLV-1 provirus. Among the HTLV-1-encoded viral genes, HBZ is the only gene that is constitutively expressed in all ATL cases. Recent studies have demonstrated that HBZ plays an essential role in oncogenesis by regulating viral transcription and modulating multiple host factors, as well as cellular signaling pathways, that contribute to the development and continued growth of cancer. In this article, I summarize the current knowledge of the oncogenic function of HBZ in cell proliferation, apoptosis, T-cell differentiation, immune escape, and HTLV-1 pathogenesis.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Carcinogenesis; Cell Transformation, Neoplastic; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Retroviridae Proteins
PubMed: 26848677
DOI: 10.3390/v8020034 -
Frontiers in Immunology 2022Previous studies have demonstrated the development of pulmonary impairment in individuals infected with human T-lymphotropic virus type 1 (HTLV-1). Complications, such... (Review)
Review
Previous studies have demonstrated the development of pulmonary impairment in individuals infected with human T-lymphotropic virus type 1 (HTLV-1). Complications, such as alveolitis and bronchiectasis, were found in individuals who developed tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP-HAM) due to chronic inflammation. These patients exhibited increased levels of lymphocytes (CD4+ and CD25+), cytokines (IL-2, IL-12, and IFN-γ), inflammatory chemokines (MIP-1α and IP-10), and cell adhesion molecules (ICAM-1) in the bronchoalveolar lavage fluid, with the result of chronic inflammation and lung injury. The main lesions observed at Chest high-resolution computed tomography were centrilobular nodules, parenchymal bands, lung cysts, bronchiectasis, ground-glass opacity, mosaic attenuation, and pleural thickening. It can lead to progressive changes in pulmonary function with the development of restrictive and obstructive diseases. Recent studies suggest a causal relationship between HTLV-1 and pulmonary diseases, with intensification of lesions and progressive decrease in pulmonary function. This summary updates a previous publication and addresses the general lack of knowledge regarding the relationship between TSP-HAM and pulmonary disease, providing direction for future work and the management of these individuals.
Topics: Bronchiectasis; Human T-lymphotropic virus 1; Humans; Inflammation; Lung Diseases; Lung Injury; Paraparesis, Tropical Spastic
PubMed: 35844492
DOI: 10.3389/fimmu.2022.914498 -
Virus Research Oct 2014Human T-lymphotropic virus (HTLV) infection is a high risk factor for lymphoproliferative, inflammatory, and infectious disorders. The epidemiology of HTLV-I, II in... (Review)
Review
Human T-lymphotropic virus (HTLV) infection is a high risk factor for lymphoproliferative, inflammatory, and infectious disorders. The epidemiology of HTLV-I, II in industrialized countries has been intensively investigated, and mandatory screening of blood supplies for HTLV-I/II was implemented in mid-1980s in most developed and several developing countries, yet no expanding investigation has been executed in China so far and also been considered as a non-endemic region. However, Gessain et al. reported that the current number of HTLV carriers in the highly populated China is very probably much higher. Therefore, gaining insight into the epidemiology of HTLV infections is essential for avoiding HTLV-induced risk. To introduce the history and renew the HTLV infection in China, we reviewed literatures and conducted an investigation among blood donors in 9 provinces in China. Concluded from the historical and renewed data, the HTLV screen in China can be divided into three stages.
Topics: China; HTLV-I Infections; History, 20th Century; History, 21st Century; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Humans
PubMed: 25109546
DOI: 10.1016/j.virusres.2014.07.036 -
Viruses Jan 2016Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular... (Review)
Review
Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular pathology of virus-induced cancers. HTLV-1 is the etiological agent of an adult T-cell leukemia (ATL) and can lead to a variety of neurological pathologies, including HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP). The ability to treat the aggressive ATL subtypes remains inadequate. HTLV-1 replicates by (1) an infectious cycle involving virus budding and infection of new permissive target cells and (2) mitotic division of cells harboring an integrated provirus. Virus replication initiates host antiviral immunity and the checkpoint control of cell proliferation, but HTLV-1 has evolved elegant strategies to counteract these host defense mechanisms to allow for virus persistence. The study of the molecular biology of HTLV-1 replication has provided crucial information for understanding HTLV-1 replication as well as aspects of viral replication that are shared between HTLV-1 and human immunodeficiency virus type 1 (HIV-1). Here in this review, we discuss the various stages of the virus replication cycle-both foundational knowledge as well as current updates of ongoing research that is important for understanding HTLV-1 molecular pathogenesis as well as in developing novel therapeutic strategies.
Topics: Animals; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Virus Replication
PubMed: 26828513
DOI: 10.3390/v8020031 -
Frontiers in Immunology 2023The African continent is considered the largest high endemic area for the oncogenic retrovirus HTLV-1 with an estimated two to five million infected individuals.... (Review)
Review
The African continent is considered the largest high endemic area for the oncogenic retrovirus HTLV-1 with an estimated two to five million infected individuals. However, data on epidemiological aspects, in particular prevalence, risk factors and geographical distribution, are still very limited for many regions: on the one hand, few large-scale and representative studies have been performed and, on the other hand, many studies do not include confirmatory tests, resulting in indeterminate serological results, and a likely overestimation of HTLV-1 seroprevalence. For this review, we included the most robust studies published since 1984 on the prevalence of HTLV-1 and the two major diseases associated with this infection in people living in Africa and the Indian Ocean islands: adult T-cell leukemia (ATL) and tropical spastic paraparesis or HTLV-1-associated myelopathy (HAM/TSP). We also considered most of the book chapters and abstracts published at the 20 international conferences on HTLV and related viruses held since 1985, as well as the results of recent meta-analyses regarding the status of HTLV-1 in West and sub-Saharan Africa. Based on this bibliography, it appears that HTLV-1 distribution is very heterogeneous in Africa: The highest prevalences of HTLV-1 are reported in western, central and southern Africa, while eastern and northern Africa show lower prevalences. In highly endemic areas, the HTLV-1 prevalence in the adult population ranges from 0.3 to 3%, increases with age, and is highest among women. In rural areas of Gabon and the Democratic Republic of the Congo (DRC), HTLV-1 prevalence can reach up to 10-25% in elder women. HTLV-1-associated diseases in African patients have rarely been reported on hospital wards, by local physicians. With the exception of the Republic of South Africa, DRC and Senegal, most reports on ATL and HAM/TSP in African patients have been published by European and American clinicians and involve immigrants or medical returnees to Europe (France and the UK) and the United States. There is clearly a huge underreporting of these diseases on the African continent. The genetic diversity of HTLV-1 is greatest in Africa, where six distinct genotypes (a, b, d, e, f, g) have been identified. The most frequent genotype in central Africa is genotype b. The other genotypes found in central Africa (d, e, f and g) are very rare. The vast majority of HTLV-1 strains from West and North Africa belong to genotype a, the so-called 'Cosmopolitan' genotype. These strains form five clades roughly reflecting the geographic origin of the infected individuals. We have recently shown that some of these clades are the result of recombination between a-WA and a-NA strains. Almost all sequences from southern Africa belong to Transcontinental a-genotype subgroup.
Topics: Adult; Humans; Female; Aged; Human T-lymphotropic virus 1; HTLV-I Infections; Seroepidemiologic Studies; Hospital Distribution Systems; Paraparesis, Tropical Spastic; Genetic Variation; South Africa
PubMed: 36817417
DOI: 10.3389/fimmu.2023.1043600