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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 -
International Journal of Molecular... May 2023CD30, a member of the tumor necrosis factor receptor superfamily, plays roles in pro-survival signal induction and cell proliferation in peripheral T-cell lymphoma... (Review)
Review
CD30, a member of the tumor necrosis factor receptor superfamily, plays roles in pro-survival signal induction and cell proliferation in peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). Previous studies have identified the functional roles of CD30 in CD30-expressing malignant lymphomas, not only PTCL and ATL, but also Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and a portion of diffuse large B-cell lymphoma (DLBCL). CD30 expression is often observed in virus-infected cells such as human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is capable of immortalizing lymphocytes and producing malignancy. Some ATL cases caused by HTLV-1 infection overexpress CD30. However, the molecular mechanism-based relationship between CD30 expression and HTLV-1 infection or ATL progression is unclear. Recent findings have revealed super-enhancer-mediated overexpression at the CD30 locus, CD30 signaling via trogocytosis, and CD30 signaling-induced lymphomagenesis in vivo. Successful anti-CD30 antibody-drug conjugate (ADC) therapy for HL, ALCL, and PTCL supports the biological significance of CD30 in these lymphomas. In this review, we discuss the roles of CD30 overexpression and its functions during ATL progression.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; Hodgkin Disease; Lymphoma, Large B-Cell, Diffuse; Human T-lymphotropic virus 1; HTLV-I Infections; Disease Progression
PubMed: 37240076
DOI: 10.3390/ijms24108731 -
Retrovirology May 2023Most proteins expressed by endogenous and exogenous retroviruses are encoded in the sense (positive) strand of the genome and are under the control of regulatory... (Review)
Review
Most proteins expressed by endogenous and exogenous retroviruses are encoded in the sense (positive) strand of the genome and are under the control of regulatory elements within the 5' long terminal repeat (LTR). A number of retroviral genomes also encode genes in the antisense (negative) strand and their expression is under the control of negative sense promoters within the 3' LTR. In the case of the Human T-cell Lymphotropic Virus 1 (HTLV-1), the antisense protein HBZ has been shown to play a critical role in the virus lifecycle and in the pathogenic process, while the function of the Human Immunodeficiency Virus 1 (HIV-1) antisense protein ASP remains unknown. However, the expression of 3' LTR-driven antisense transcripts is not always demonstrably associated with the presence of an antisense open reading frame encoding a viral protein. Moreover, even in the case of retroviruses that do express an antisense protein, such as HTLV-1 and the pandemic strains of HIV-1, the 3' LTR-driven antisense transcript shows both protein-coding and noncoding activities. Indeed, the ability to express antisense transcripts appears to be phylogenetically more widespread among endogenous and exogenous retroviruses than the presence of a functional antisense open reading frame within these transcripts. This suggests that retroviral antisense transcripts may have originated as noncoding molecules with regulatory activity that in some cases later acquired protein-coding function. Here, we will review examples of endogenous and exogenous retroviral antisense transcripts, and the ways through which they benefit viral persistence in the host.
Topics: Humans; Human T-lymphotropic virus 1; Deltaretrovirus; Viral Proteins; Promoter Regions, Genetic; HIV-1
PubMed: 37194028
DOI: 10.1186/s12977-023-00622-x -
BMC Infectious Diseases May 2023Numerous vaccination research experiments have been conducted on non-primate hosts to prevent or control HTLV-1 infection. Therefore, reviewing recent advancements for...
BACKGROUND
Numerous vaccination research experiments have been conducted on non-primate hosts to prevent or control HTLV-1 infection. Therefore, reviewing recent advancements for status assessment and strategic planning of future preventative actions to reduce HTLV-1 infection and its consequences would be essential.
METHODS
MEDLINE, Scopus, Web of Science, and Clinicaltrials.gov were searched from each database's inception through March 27, 2022. All original articles focusing on developing an HTLV-1 vaccine candidate were included.
RESULTS
A total of 47 studies were included. They used a variety of approaches to develop the HTLV-1 vaccine, including DNA-based, dendritic-cell-based, peptide/protein-based, and recombinant vaccinia virus approaches. The majority of the research that was included utilized Tax, Glycoprotein (GP), GAG, POL, REX, and HBZ as their main peptides in order to develop the vaccine. The immunization used in dendritic cell-based investigations, which were more recently published, was accomplished by an activated CD-8 T-cell response. Although there hasn't been much attention lately on this form of the vaccine, the initial attempts to develop an HTLV-1 immunization depended on recombinant vaccinia virus, and the majority of results seem positive and effective for this type of vaccine. Few studies were conducted on humans. Most of the studies were experimental studies using animal models. Adenovirus, Cytomegalovirus (CMV), vaccinia, baculovirus, hepatitis B, measles, and pox were the most commonly used vectors.
CONCLUSIONS
This systematic review reported recent progression in the development of HTLV-1 vaccines to identify candidates with the most promising preventive and therapeutic effects.
Topics: Animals; Humans; Human T-lymphotropic virus 1; HTLV-I Infections; T-Lymphocytes; Vaccinia virus; Viral Vaccines; Peptides
PubMed: 37170214
DOI: 10.1186/s12879-023-08289-7 -
Scientific Reports May 2023Around ten million people are infected with HTLV-1 worldwide, and 1-4% develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), characterized by an...
Around ten million people are infected with HTLV-1 worldwide, and 1-4% develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), characterized by an important degeneration of the spinal cord, which can lead to death. Distinct HLA alleles have been associated with either HAM/TSP susceptibility or protection. However, these HLA alleles set may change according to the population studied. Brazil is the second country in the number of HTLV-1-infected people and there are few reports addressing the HLA influence on HTLV-1 infection as well as on disease outcome. The objective of this study was to evaluate the influence of HLA alleles as a risk factor for HAM/TSP and the proviral load (PVL) levels, clinical progression, and death outcomes in an admixed Brazilian population. The HLA-A, -B, -C, and -DRB1 were genotyped in 375 unrelated HTLV-1-infected individuals divided into asymptomatic carriers (AC) (n = 165) and HAM/TSP (n = 210) in a longitudinal cohort from 8 to 22 years of follow-up. Because locus B deviated from Hardy-Weinberg Equilibrium for the study groups, the results represented for HLA-B alleles were inconclusive. The alleles HLA-A*68 and -C*07 were related to HAM/TSP risk in multivariate analysis. The alleles HLA-A*33, and -A*36 were associated with protection against disease progression in HAM/TSP patients, while -C*12, -C*14, and -DRB1*08 were associated with increased risk of death. In the AC group, the presence of, -C*06 and -DRB1*15 alleles influenced an increased PVL, in an adjusted linear regression model, while -A*30, -A*34, -C*06, -C*17 and -DRB1*09 alleles were associated with increased PVL in HAM/TSP group compared to HAM/TSP individuals not carrying these alleles. All these alleles were also related to increased PVL associated with clinical progression outcome. Increased PVL associated with the death outcome was linked to the presence of HLA-A*30. PVL has been associated with HLA, and several alleles were related in AC and HAM/TSP patients with or without interacting with clinical progression outcomes. Understanding the prognostic value of HLA in HAM/TSP pathogenesis can provide important biomarkers tools to improve clinical management and contribute to the discovery of new therapeutic interventions.
Topics: Humans; Paraparesis, Tropical Spastic; Brazil; HTLV-I Infections; Human T-lymphotropic virus 1; Disease Progression; HLA-A Antigens; Viral Load
PubMed: 37169817
DOI: 10.1038/s41598-023-34757-w -
Blood Cancer Discovery Sep 2023Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells because its accumulation is toxic. Here, we...
UNLABELLED
Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells because its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminishes the development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreases the growth of ATL cells in vitro and in vivo. MCT1/4 expression is positively correlated with TAp73 in many cancers, and MCT1/4 upregulation is associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to cancer metabolism.
SIGNIFICANCE
An antisense gene encoded in HTLV-1, HBZ, reprograms lactate metabolism and epigenetic modification by inducing TAp73 in virus-positive leukemic cells. A positive correlation between TAp73 and its target genes is also observed in many other cancer cells, suggesting that this is a common mechanism for cellular oncogenesis. This article is featured in Selected Articles from This Issue, p. 337.
Topics: Mice; Animals; Human T-lymphotropic virus 1; Basic-Leucine Zipper Transcription Factors; Leukemia-Lymphoma, Adult T-Cell; Mice, Transgenic; Epigenesis, Genetic; Lactates
PubMed: 37162520
DOI: 10.1158/2643-3230.BCD-22-0139 -
Clinical Infectious Diseases : An... Sep 2023Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurological condition characterized by progressive...
BACKGROUND
Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurological condition characterized by progressive myelopathic symptoms including spasticity, pain, weakness, and urinary symptoms, without proven treatments. Mogamulizumab (MOG) is a monoclonal antibody that binds CCR4 and leads to the clearance of HTLV-1-infected CCR4+ cells. A phase 1-2a study in Japan evaluated MOG for the treatment of HAM/TSP and reported decreases in HTLV-1 proviral load and neuroinflammatory markers, with clinical improvement in some participants.
METHODS
We administered MOG 0.1 mg/kg every 8 weeks to individuals with HAM/TSP as a compassionate and palliative treatment. Patients who received MOG had (1) a positive peripheral HTLV-1 antibody, (2) progressive myelopathic symptoms, and (3) a diagnosis of HAM/TSP.
RESULTS
Four female patients, ages 45-68, received MOG (range, 2-6 infusions) between 1 November 2019 and 30 November 2022. Two patients with <3 years of symptoms had milder disease, with Osame scores <4. The other 2, with >7 years of symptoms, had Osame scores >5. One patient, with 6 total treatments, received dose-reduced MOG after she developed a rash at the initial dose. The 2 patients with milder baseline disease reported symptomatic improvement and saw reductions in Osame and/or modified Ashworth scale scores during follow-up. The other 2 patients showed no improvement. All 4 developed rashes after receiving MOG-a treatment-limiting event in some cases.
CONCLUSIONS
Clinical trials are needed including diverse patient populations to assess the potential role of MOG for HAM/TSP. Our findings may help inform the development of these trials.
Topics: Humans; Female; Paraparesis, Tropical Spastic; Human T-lymphotropic virus 1; Antibodies, Monoclonal, Humanized; Exanthema; Viral Load
PubMed: 37157862
DOI: 10.1093/cid/ciad281 -
BMC Musculoskeletal Disorders May 2023Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but...
BACKGROUND
Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date.
CASE PRESENTATION
A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment.
CONCLUSION
This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.
Topics: Humans; Adult; Female; Aged; Paraparesis, Tropical Spastic; Myopathies, Nemaline; Human T-lymphotropic virus 1; HIV Infections; Muscle Fibers, Skeletal; Bone Marrow Diseases
PubMed: 37149561
DOI: 10.1186/s12891-023-06461-3 -
Blood Cancer Journal May 2023Adult T cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with human T cell leukemia virus type 1 (HTLV-1). The viral oncoprotein...
Adult T cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with human T cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax initiates T cell transformation through activation of critical cellular pathways, including NF-κB. Unexpectedly, Tax protein is not detectable in most ATL cells, in contrast to the HTLV-1 HBZ protein which antagonizes Tax effects. Here, we demonstrate that primary ATL cells from patients with acute or chronic ATL express very low levels of Tax mRNA and protein. Critically, survival of these primary ATL cells is dependent on continued Tax expression. Mechanistically, Tax extinction results in reversal of NF-κB activation, P53/PML activation and apoptosis. Tax drives interleukin-10 (IL-10) expression and recombinant IL-10 rescues the survival of tax-depleted primary ATL cells. These results demonstrate the critical role of continued Tax and IL-10 expression for the survival of primary ATL cells, highlighting their relevance as therapeutic targets.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; NF-kappa B; Interleukin-10; Lymphoma
PubMed: 37137914
DOI: 10.1038/s41408-023-00841-7 -
Frontiers in Immunology 2023Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called 'cell-free' DNA (cfDNA) released...
INTRODUCTION
Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called 'cell-free' DNA (cfDNA) released from dying malignant cells encodes cancer-associated mutations. Thus, minimally invasive sampling of cfDNA in blood plasma can be used to diagnose, characterise and longitudinally monitor solid tumours at remote sites in the body. ~5% of carriers of Human T cell leukaemia virus type 1 (HTLV-1) develop Adult T cell leukaemia/lymphoma (ATL), and a similar percentage develop an inflammatory CNS disease, HTLV-1 associated myelopathy (HAM). In both ATL and HAM, high frequencies of HTLV-1 infected cells are present in the affected tissue: each carrying an integrated DNA copy of the provirus. We hypothesised that turnover of infected cells results in the release of HTLV-1 proviruses in cfDNA, and that analysis of cfDNA from infected cells in HTLV-1 carriers might contain clinically useful information pertaining to inaccessible sites in the body- e.g. for early detection of primary or relapsing localised lymphoma type ATL. To evaluate the feasibility of this approach, we tested for HTLV-1 proviruses in blood plasma cfDNA.
METHODS
CfDNA (from blood plasma) and genomic DNA (gDNA, from peripheral blood mononuclear cells, PBMC) was isolated from blood from 6 uninfected controls, 24 asymptomatic carriers (AC), 21 patients with HAM and 25 patients with ATL. Proviral (HTLV-1 ) and human genomic DNA (the beta globin gene, ) targets were quantified by qPCR using primer pairs optimised for fragmented DNA.
RESULTS
Pure, high quality cfDNA was successfully extracted from blood plasma of all study participants. When compared with uninfected controls, HTLV-1 carriers had higher concentrations of cfDNA circulating in their blood plasma. Patients with ATL who were not in remission had the highest levels of blood plasma cfDNA in any group studied. HTLV-1 proviral DNA was detected in 60/70 samples obtained from HTLV-1 carriers. The proviral load (percentage of cells carrying proviruses) was approximately tenfold lower in plasma cfDNA than in PBMC genomic DNA, and there was a strong correlation between the proviral load in cfDNA and PBMC genomic DNA in HTLV-1 carriers that did not have ATL. cfDNA samples in which proviruses were undetectable also had very low proviral load in PBMC genomic DNA. Finally, detection of proviruses in cfDNA of patients with ATL was predictive of clinical status: patients with evolving disease had higher than expected total amount of proviruses detectable in plasma cfDNA.
DISCUSSION
We demonstrated that (1) HTLV-1 infection is associated with increased levels of blood plasma cfDNA, (2) proviral DNA is released into blood plasma cfDNA in HTLV-1 carriers and (3) proviral burden in cfDNA correlates with clinical status, raising the possibility of developing assays of cfDNA for clinical use in HTLV-1 carriers.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Proviruses; Paraparesis, Tropical Spastic; Leukocytes, Mononuclear; DNA, Viral; Neoplasm Recurrence, Local; Liquid Biopsy; Cell-Free Nucleic Acids
PubMed: 37114063
DOI: 10.3389/fimmu.2023.1150285