HTLV-1 infected T cells cause bone loss via small extracellular vesicles.

Adult T cell leukaemia (ATL), caused by infection with human T- lymphotropic virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T leads to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone.

An HTLV-1 envelope mRNA vaccine is immunogenic and protective in New Zealand rabbits.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma, a severe and fatal CD4+ T-cell malignancy. Additionally, HTLV-1 can lead to a chronic progressive neurodegenerative disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis. Unfortunately, the prognosis for HTLV-1-related diseases is generally poor, and effective treatment options are limited.

The Pleiotropic Effects of YBX1 on HTLV-1 Transcription.

HTLV-1 is an oncogenic human retrovirus and the etiologic agent of the highly aggressive ATL malignancy. Two viral genes, and , are individually linked to oncogenic transformation and play an important role in the pathogenic process. Consequently, regulation of HTLV-1 gene expression is a central feature in the viral lifecycle and directly contributes to its pathogenic potential.

Retroviral b-Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation.

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neuroinflammatory demyelinating condition of the spinal cord. We have previously shown that aberrant expression and activity of immune checkpoint (ICP) molecules such as PD-1 and PD-L1/PD-L2, negatively associates with the cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPs can exist in a soluble cell-free form and can be carried on extracellular vesicles (EVs) and exosomes (small EVs, <300nm) while maintaining their immunomodulatory activity.

Upregulation of Neuropilin-1 Inhibits HTLV-1 Infection.

Infection with human T-cell leukemia virus type 1 (HTLV-1) can produce a spectrum of pathological effects ranging from inflammatory disorders to leukemia. In vivo, HTLV-1 predominantly infects CD4 T-cells. Infectious spread within this population involves the transfer of HTLV-1 virus particles from infected cells to target cells only upon cell-to-cell contact.

HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic cells. Our previous work found Hbz protein is dispensable for virus-mediated T-cell immortalization but enhances viral persistence. We and others have also shown that hbz mRNA promotes T-cell proliferation.

HBZ upregulates myoferlin expression to facilitate HTLV-1 infection.

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.

The PRMT5 inhibitor EPZ015666 is effective against HTLV-1-transformed T-cell lines and .

Human T-cell leukemia virus type 1 (HTLV-1) is the infectious cause of adult T-cell leukemia/lymphoma (ATL), an extremely aggressive and fatal malignancy of CD4 T-cells. Due to the chemotherapy-resistance of ATL and the absence of long-term therapy regimens currently available for ATL patients, there is an urgent need to characterize novel therapeutic targets against this disease. Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme that is directly involved in the pathogenesis of multiple different lymphomas through the transcriptional regulation of relevant oncogenes.

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2.

The genome of retroviruses contains two promoter elements (called long terminal repeat or LTR) at the 5' and 3' end of their genome. Although the expression of retroviral genes generally depends on the promoter located in the 5' LTR, the 3' LTR also has promoter activity responsible for producing antisense transcripts. These natural antisense transcripts (NATs) are a class of RNA molecules transcribed from the opposite strand of a protein-coding gene.

HTLV-1 intragenic viral enhancer influences immortalization phenotype , but is dispensable for persistence and disease development in animal models.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL) and chronic neurological disease. The disparity between silenced sense transcription versus constitutively active antisense (Hbz) transcription from the integrated provirus is not fully understood. The presence of an internal viral enhancer has recently been discovered in the Tax gene near the 3' long terminal repeat (LTR) of HTLV-1.

The Past, Present, and Future of a Human T-Cell Leukemia Virus Type 1 Vaccine.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus which causes a lifelong infection. An estimated 5-10 million persons are infected with HTLV-1 worldwide - a number which is likely higher due to lack of reliable epidemiological data. Most infected individuals remain asymptomatic; however, a portion of HTLV-1-positive individuals will develop an aggressive CD4+ T-cell malignancy called adult T-cell leukemia/lymphoma (ATL), or a progressive neurodegenerative disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Regulation of HTLV-1 transformation.

Human T-cell leukemia virus type 1 (HTLV-1) is the only identified oncogenic human retrovirus. HTLV-1 infects approximately 5-10 million people worldwide and is the infectious cause of adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), dermatitis, and uveitis. Unlike other oncogenic retroviruses, HTLV-1 does not capture a cellular proto-oncogene or induce proviral insertional mutagenesis.

Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4 T-cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neurological disease. Disease progression in infected individuals is the result of HTLV-1-driven clonal expansion of CD4 T-cells and is generally associated with the activities of the viral oncoproteins Tax and Hbz. A closely related virus, HTLV-2, exhibits similar genomic features and the capacity to transform T-cells, but is non-pathogenic.

CRISPR Genome Editing Applied to the Pathogenic Retrovirus HTLV-1.

CRISPR editing of retroviral proviruses has been limited to HIV-1. We propose human T-cell leukemia virus type 1 (HTLV-1) as an excellent model to advance CRISPR/Cas9 genome editing technologies against actively expressing and latent retroviral proviruses. HTLV-1 is a tumorigenic human retrovirus responsible for the development of both leukemia/lymphoma (ATL) and a neurological disease (HAM/TSP).

Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone.

Adult T-cell leukemia/lymphoma has a unique relationship to bone including latency in the marrow, and development of bone invasion, osteolytic tumors and humoral hypercalcemia of malignancy. To study these conditions, we established and characterized a novel mouse model of ATL bone metastasis. Patient-derived ATL cell lines including three that do not express HTLV-1 oncoprotein Tax (ATL-ED, RV-ATL, TL-Om1), an transformed human T-cell line with high Tax expression (HT-1RV), and an HTLV-1 negative T-cell lymphoma (Jurkat) were injected intratibially into NSG mice, and were capable of proliferating and modifying the bone microenvironment.

HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo.

Background: Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact mechanism(s) through which latency and disease progression are regulated are not fully understood. CCCTC-binding factor (CTCF) is an 11-zinc finger, sequence-specific, DNA-binding protein with thousands of binding sites throughout mammalian genomes.

HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia.

Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models.

CRISPR/Cas9 Genome Editing to Disable the Latent HIV-1 Provirus.

HIV-1 infection can be successfully controlled with anti-retroviral therapy (ART), but is not cured. A reservoir of cells harboring transcriptionally silent integrated provirus is able to reestablish replicating infection if ART is stopped. Latently HIV-1 infected cells are rare, but may persist for decades.

SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice.

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase (dNTPase) and functions as a negative regulator in the efficacy of cytarabine treatment of acute myeloid leukemia (AML). We have reported that SAMHD1 knockout (KO) increased the activity of phosphoinositide 3-kinase (PI3K) in AML-derived THP-1 cells and attenuated their ability to form subcutaneous tumors in xenografted immunodeficient mice. However, the functional significance of SAMHD1 in controlling AML leukemogenesis remains unclear.

Stability of the HTLV-1 Antisense-Derived Protein, HBZ, Is Regulated by the E3 Ubiquitin-Protein Ligase, UBR5.

Human T-cell leukemia virus type 1 (HTLV-1) encodes a protein derived from the antisense strand of the proviral genome designated HBZ (HTLV-1 basic leucine zipper factor). HBZ is the only viral gene consistently expressed in infected patients and adult T-cell leukemia/lymphoma (ATL) tumor cell lines. It functions to antagonize many activities of the Tax viral transcriptional activator, suppresses apoptosis, and supports proliferation of ATL cells.

Human Genetic Determinants of Viral Diseases.

Much progress has been made in the identification of specific human gene variants that contribute to enhanced susceptibility or resistance to viral diseases. Herein we review multiple discoveries made with genome-wide or candidate gene approaches that have revealed significant insights into virus-host interactions. Genetic factors that have been identified include genes encoding virus receptors, receptor-modifying enzymes, and a wide variety of innate and adaptive immunity-related proteins.

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis.

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking.

Human T-cell leukemia virus-associated malignancy.

Human T-cell leukemia virus type 1 (HTLV-1) is a tumorigenic delta retrovirus and the causative infectious agent of a non-Hodgkin's peripheral T-cell malignancy called adult T-cell leukemia/lymphoma (ATL). ATL develops in approximately 5% of infected individuals after a significant clinical latency period of several decades. Clinical classifications of ATL include smoldering, chronic, lymphoma, and acute subtypes, with varying median survival ranges of a few months to several years.

Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis.

Unlabelled: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cells in vitro but have distinct pathological outcomes in vivo. HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistence in vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells, hbz is often the only viral gene expressed.