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International Journal of Molecular... May 2021Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently... (Review)
Review
Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4 T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8 cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.
Topics: CD4-Positive T-Lymphocytes; Gene Expression Regulation, Viral; Gene Products, tax; Histone Deacetylase Inhibitors; Histones; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Phosphorylation; Positive Transcriptional Elongation Factor B; Virus Latency
PubMed: 34073995
DOI: 10.3390/ijms22115545 -
Medecine Sciences : M/S Apr 2022Retroviruses exploit the RNA polymerase II transcription machinery for the transcription of their genes. This is the case of Human T-lymphotropic virus type 1 (HTLV-1),... (Review)
Review
Retroviruses exploit the RNA polymerase II transcription machinery for the transcription of their genes. This is the case of Human T-lymphotropic virus type 1 (HTLV-1), the retrovirus responsible for adult T-cell leukemia and for various inflammatory diseases. HTLV-1 transcription is under the control of the viral protein Tax, which exhibits an original mode of action since it does not rely on direct promoter interaction but rather on the recruitment of various cellular factors and cofactors of transcription. The factors that Tax recruits are involved in the initial step of promoter activation but also in the subsequent steps of the transcription process itself. This review describes this particular mechanism of viral transcription, from the epigenetic release of the viral promoter to the elongation of the neosynthesized viral silencing transcripts.
Topics: Cell Line; Gene Products, tax; Human T-lymphotropic virus 1; Humans; Promoter Regions, Genetic
PubMed: 35485896
DOI: 10.1051/medsci/2022039 -
MSphere Sep 2020Bats are the reservoir for a large number of zoonotic viruses, including members of (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2), (Hendra...
Bats are the reservoir for a large number of zoonotic viruses, including members of (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2), (Hendra and Nipah viruses), (rabies virus), and (Ebola virus) as exemplars. Many retroviruses, such as human immunodeficiency virus, are similarly zoonotic; however, only infectious exogenous gammaretroviruses have recently been identified in bats. Here, viral metagenomic sequencing of samples from bats submitted for rabies virus testing, largely due to human exposure, identified a novel, highly divergent exogenous from a big brown bat () in South Dakota. The virus sequence, corresponding to deltaretrovirus (EfDRV), comprised a nearly complete coding region comprised of canonical 5'-----3' genes with 37% to 51% identity to human T-lymphotropic virus (HTLV), an infectious retrovirus that causes T-cell lymphoma. A putative gene with 27% identity to HTLV was located downstream of the gene along with a gene harbored in an alternative reading frame which possessed a conserved domain for an Epstein-Barr virus nuclear antigen involved in gene transactivation, suggesting a regulatory function similar to that of the deltaretrovirus gene. A TaqMan reverse transcriptase PCR (RT-PCR) targeting the gene identified 4/60 (6.7%) bats as positive for EfDRV, which, combined with a search of the genome that failed to identify sequences with homology to EfDRV, suggests that EfDRV is an infectious exogenous virus. As all known members of can cause malignancies and is widely distributed in the Americas, often with a colonial roosting behavior in human dwellings, further studies are needed to investigate potential zoonosis. Bats host a large numbers of viruses, many of which are zoonotic. In the United States, the big brown bat () is widely distributed and lives in small colonies that roost in cavities, often in human dwellings, leading to frequent human interaction. Viral metagenomic sequencing of samples from an bat submitted for rabies testing identified the first exogenous bat The deltaretrovirus (EfDRV) genome consists of the typical deltaretrovial 5'-----3' genes along with genes encoding two putative transcriptional transactivator proteins distantly related to the Tax protein of human T-cell lymphotrophic virus and nuclear antigen 3B of Epstein-Barr virus. Searches of the genome sequence failed to identify endogenous EfDRV. RT-PCR targeting the EfDRV gene identified 4/60 (6.7%) bats with positive results. Together, these results suggest that EfDRV is exogenous. As all members of are associated with T- and B-cell malignancies or neurologic disease, further studies on possible zoonosis are warranted.
Topics: Animals; Chiroptera; Deltaretrovirus; Gene Products, tax; Genome, Viral; Humans; RNA, Viral; South Dakota; United States; Zoonoses
PubMed: 32968009
DOI: 10.1128/mSphere.00902-20 -
Seminars in Diagnostic Pathology Mar 2020Human T cell leukemia virus type 1 (HTLV-1) is a horizontally transmitted virus infection of CD4+ lymphocytes which causes adult T cell leukemia-lymphoma (ATLL) and... (Review)
Review
Human T cell leukemia virus type 1 (HTLV-1) is a horizontally transmitted virus infection of CD4+ lymphocytes which causes adult T cell leukemia-lymphoma (ATLL) and HTLV-associated myelopathy (HAM). The viral genome encodes two oncoproteins, transactivator protein (Tax) and helix basic zipper protein (HBZ), which are considered tumor initiator and maintenance factors, respectively. Tax is the primary inducer of clonal infected T cell expansion, and genetic instability. The immune response to Tax results in the selection of cells with little or no Tax expression, which have undergone genetic and epigenetic alterations that promote T cell activation, proliferation, and resistance to apoptosis. This selection of malignant cells occurs over several decades in 5% of infected individuals. Novel insights into the molecular details of each of these events has led to targeted therapies for ATLL.
Topics: Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell
PubMed: 31103249
DOI: 10.1053/j.semdp.2019.04.003 -
Retrovirology Jun 2023Bovine Leukemia Virus (BLV) is the etiological agent of enzootic bovine leukosis, a disease characterized by the neoplastic proliferation of B cells in cattle. While... (Review)
Review
Bovine Leukemia Virus (BLV) is the etiological agent of enzootic bovine leukosis, a disease characterized by the neoplastic proliferation of B cells in cattle. While most European countries have introduced efficient eradication programs, BLV is still present worldwide and no treatment is available. A major feature of BLV infection is the viral latency, which enables the escape from the host immune system, the maintenance of a persistent infection and ultimately the tumoral development. BLV latency is a multifactorial phenomenon resulting in the silencing of viral genes due to genetic and epigenetic repressions of the viral promoter located in the 5' Long Terminal Repeat (5'LTR). However, viral miRNAs and antisense transcripts are expressed from two different proviral regions, respectively the miRNA cluster and the 3'LTR. These latter transcripts are expressed despite the viral latency affecting the 5'LTR and are increasingly considered to take part in tumoral development. In the present review, we provide a summary of the experimental evidence that has enabled to characterize the molecular mechanisms regulating each of the three BLV transcriptional units, either through cis-regulatory elements or through epigenetic modifications. Additionally, we describe the recently identified BLV miRNAs and antisense transcripts and their implications in BLV-induced tumorigenesis. Finally, we discuss the relevance of BLV as an experimental model for the closely related human T-lymphotropic virus HTLV-1.
Topics: Animals; Cattle; Humans; Transcription Factors; Leukemia Virus, Bovine; Gene Expression Regulation; MicroRNAs; Epigenesis, Genetic; Enzootic Bovine Leukosis
PubMed: 37268923
DOI: 10.1186/s12977-023-00623-w -
Frontiers in Immunology 2022Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus which mainly infects CD4 T cells and causes adult T-cell leukemia/lymphoma (ATL), is primarily transmitted... (Review)
Review
Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus which mainly infects CD4 T cells and causes adult T-cell leukemia/lymphoma (ATL), is primarily transmitted direct cell-to-cell transmission. This feature generates a wide variety of infected clones in hosts, which are maintained clonal proliferation, resulting in the persistence and survival of the virus. The maintenance of the pool of infected cells is achieved by sculpting the immunophenotype of infected cells and modulating host immune responses to avoid immune surveillance. Here, we review the processes undertaken by HTLV-1 to modulate and subvert host immune responses which contributes to viral persistence and development of ATL.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Carcinogenesis; Immunophenotyping; T-Lymphocytes
PubMed: 36300109
DOI: 10.3389/fimmu.2022.991928 -
The Lancet. Infectious Diseases Jan 2021Human T-cell lymphotropic virus type-1 (HTLV-1) has a large global burden and in some key communities, such as Indigenous Australians living in remote areas, greater... (Review)
Review
Human T-cell lymphotropic virus type-1 (HTLV-1) has a large global burden and in some key communities, such as Indigenous Australians living in remote areas, greater than 45% of people are infected. Despite HTLV-1 causing serious malignancy and myelopathic paraparesis, and a significant association with a range of inflammatory comorbidities and secondary infections that shorten lifespan, few biomedical interventions are available. HTLV-1 starkly contrasts with other blood-borne sexually transmitted viral infections, such as, HIV, hepatitis B virus, and hepatitis C virus, with no antiviral treatments that reduce virus-infected cells, no rapid diagnostics or biomarker assays suitable for use in remote settings, and no effective vaccine. We review how the replication strategies and molecular properties of HTLV-1 establish a long-term stealthy viral pathogenesis through a fine-tuned balance of persistence, immune cell dysfunction, and proliferation of proviral infected cells that collectively present robust barriers to treatment and prevention. An understanding of the nature of the HTLV-1 provirus and opposing actions of viral-coded negative-sense HBZ and positive-sense regulatory proteins Tax, p12 and its cleaved product p8, and p30, is needed to improve the biomedical tools for preventing transmission and improving the long-term health of people with this lifelong infection.
Topics: Australia; Gene Expression Regulation, Viral; HTLV-I Infections; Host-Pathogen Interactions; Human T-lymphotropic virus 1; Humans; Recurrence; T-Lymphocytes
PubMed: 32986997
DOI: 10.1016/S1473-3099(20)30328-5 -
Retrovirology Feb 2020HTLV-1 was the first described human retrovirus and was soon found to be associated with severe clinical diseases, including a devastating lymphoma/leukemia and other... (Review)
Review
HTLV-1 was the first described human retrovirus and was soon found to be associated with severe clinical diseases, including a devastating lymphoma/leukemia and other inflammatory diseases. Although HTLV-2 is not usually pathogenic, it is widely distributed among native Indian populations in Brazil, particularly in the Amazon region of the country. Presently, HTLV spreads mainly by the sexual route and from mother to child, and virus persistence is an active biological factor aiding its transmission. Recently, the use of illicit drugs has been shown to be an additional risk factor, showing the influence of new habits on the epidemiology of HTLV in the region. Despite the detection of the virus in several different populations in the Amazon region of Brazil for almost 30 years, the exact prevalence of HTLV-1/2 is not well defined. The original biases in sampling and the selection of epidemiologically unsuitable populations were commonly repeated in most prevalence studies, generating unreliable and conflicting figures that do not represent the actual prevalence of HTLV. The improvements in clinical and laboratory facilities have resulted in the description of several clinical manifestations that were previously unknown in the region. The extent of the spread of the virus must be defined in this region, which is the largest geographical area of the country. As prophylaxis advances toward the use of vaccines against HTLV-1, it is important to determine who is at risk of being infected and developing a disease to successfully implement preventive measures, particularly as proposals are made to eradicate the virus among humans.
Topics: Brazil; Female; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Infectious Disease Transmission, Vertical; Phylogeny; Prevalence
PubMed: 32059740
DOI: 10.1186/s12977-020-0512-z -
Viruses Oct 2021Bovine leukaemia virus (BLV) is a deltaretrovirus that is closely related to human T-cell leukaemia virus types 1 and 2 (HTLV-1 and -2). It causes enzootic bovine... (Review)
Review
Bovine leukaemia virus (BLV) is a deltaretrovirus that is closely related to human T-cell leukaemia virus types 1 and 2 (HTLV-1 and -2). It causes enzootic bovine leukosis (EBL), which is the most important neoplastic disease in cattle. Most BLV-infected cattle are asymptomatic, which potentiates extremely high shedding rates of the virus in many cattle populations. Approximately 30% of them show persistent lymphocytosis that has various clinical outcomes; only a small proportion of animals (less than 5%) exhibit signs of EBL. BLV causes major economic losses in the cattle industry, especially in dairy farms. Direct costs are due to a decrease in animal productivity and in cow longevity; indirect costs are caused by restrictions that are placed on the import of animals and animal products from infected areas. Most European regions have implemented an efficient eradication programme, yet BLV prevalence remains high worldwide. Control of the disease is not feasible because there is no effective vaccine against it. Therefore, detection and early diagnosis of the disease are essential in order to diminish its spreading and the economic losses it causes. This review comprises an overview of bovine leukosis, which highlights the epidemiology of the disease, diagnostic tests that are used and effective control strategies.
Topics: Animals; Cattle; Diagnostic Tests, Routine; Enzootic Bovine Leukosis; Female; Genome, Viral; Human T-lymphotropic virus 1; Leukemia Virus, Bovine; Prevalence; Virulence
PubMed: 34834973
DOI: 10.3390/v13112167 -
[Rinsho Ketsueki] the Japanese Journal... 2021Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I. The clinical course of ATL is heterogeneous, and...
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I. The clinical course of ATL is heterogeneous, and this condition has different types, which are as follows: acute, lymphoma, chronic, and smoldering. The chronic type is further subclassified into favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL and favorable chronic and smoldering-type ATL are defined as aggressive and indolent ATL, respectively. Newly identified prognostic indices based on clinical parameters and/or genetic predictors should be incorporated in the stratified treatment approach. The standard of care for aggressive ATL is multiagent chemotherapy, followed by allogeneic hematopoietic stem cell transplantation if applicable. Meanwhile, that for indolent ATL is watchful waiting until progression to the aggressive type. The combination of interferon-α and zidovudine is a treatment option for indolent ATL in other countries, and a confirmatory phase 3 trial is ongoing in Japan. In addition to mogamulizumab, lenalidomide, and brentuximab vedotin, which have been recently utilized in clinical practice, the use of a novel histone deacetylase (HDAC) inhibitor has been filed for approval. Moreover, an EZH1/2 inhibitor has completed the enrollment of a phase 2 trial in Japan. The standard of care for elderly patients should be established because the median age of those with newly diagnosed ATL reaches up to 70 years old.
Topics: Adult; Aged; Human T-lymphotropic virus 1; Humans; Interferon-alpha; Japan; Leukemia-Lymphoma, Adult T-Cell; Molecular Targeted Therapy
PubMed: 34349061
DOI: 10.11406/rinketsu.62.766