CD20- and CD56-Positive T-Cell Large Granular Lymphocyte Leukemia in a Human T-Cell Leukemia Virus Type 1 Carrier

A 60-year-old man was diagnosed with asymptomatic T-cell granular lymphocyte (T-LGL) leukemia in September 2006. He was serologically positive for human T-cell leukemia virus type 1 (HTLV-1). However, monoclonal integration of the HTLV-1 genome was not detected in the peripheral blood, suggesting that HTLV-1 did not contribute to the pathogenesis of T-LGL leukemia in the present case. Phenotypically, neoplastic cells of our case were CD3+, CD4*, CD8+, CD16-, CD56+, CD57*, and T-cell receptor (TCR) alphabeta+. They also coexpressed CD20 antigen with weak intensity. This represented a unique case of T-LGL leukemia showing a typical clinical and phenotypic features.     

T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Collective evidence from in vitro studies indicates that several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function, such as antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation may therefore be of importance, as also suggested by epidemiological data. Thus genetic and environmental factors together with the virus contribute to disease development. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells. The relevance of these laboratory findings is related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.     

Immunologic Control of Human T-Cell Leukemia Virus Type I and Adult T-Cell Leukemia

Host T-cell responses to human T-cell leukemia virus type I (HTLV-I) control the expansion of HTLV-I-infected cells and are determinants of the equilibrium proviral load in vivo. Insufficient T-cell responses are regarded as an immunologic risk factor for adult T-cell leukemia (ATL) because they allow increased proviral loads, which represent an epidemiologic risk factor for ATL. ATL cells from approximately half of ATL cases retain the ability to express HTLV-I Tax, a major target antigen of HTLV-I-specific cytotoxic T-lymphocytes (CTL), whereas Tax-specific CTL in ATL patients are inactive. Tax-specific CTL responses are strongly activated after hematopoietic stem cell transplantation in some ATL patients in long-term remission, indicating that HTLV-I Tax is expressed in vivo rather than being silent, and that the donor-derived T-cell system can recognize it. These findings strongly suggest that reactivation of Tax-specific CTL by vaccines may be promising for prophylaxis of ATL in the high-risk group of HTLV-I carriers and for therapy of ATL in patients whose tumor cells are capable of expressing Tax.     

Implication of the <Emphasis Type="Italic">HTLV- I bZIP Factor</Emphasis> Gene in the Leukemogenesis of Adult T-Cell Leukemia

Adult T-cell leukemia (ATL) is a leukemia derived from CD4+ mature T-cells and induced by human T-cell leukemia virus type I (HTLV-I) infection. Although previous studies have revealed many aspects of its leukemogenesis, enigmas remain about how HTLV-I transforms mature T-cells in infected individuals. Furthermore, an effective therapy for ATL has not yet been established. The critical role of a nonstructural regulatory viral protein, Tax, in transformation has been established through many molecular studies, in vitro cell culture experiments, and transgenic mouse model systems. In addition, other accessory viral proteins have been implicated in ATL pathogenesis. Recent studies of a minus strand viral gene, HTLV-I bZIP factor (HBZ), suggest it plays a role in ATL leukemogenesis. In addition to viral components, genetic and epigenetic events of the host cellular genome must be considered in developing a complete picture of the transformation process. In this review, we summarize the molecular and cellular mechanisms involved in the leukemogenesis induced by HTLV-I; we consider both viral and host cellular factors and focus particularly on the viral gene HBZ.     

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. In vitro, HTLV-1 primarily immortalizes or transforms CD4⁺ T-cells, while HTLV-2 displays a transformation tropism for CD8⁺ T-cells. This distinct tropism is recapitulated in infected people. Through comparative studies, the genetic determinant for this divergent tropism of HTLV-1/2 has been mapped to the viral envelope (Env). In this review, we explore the emerging roles for Env beyond initial viral entry and examine current perspectives on its contributions to HTLV-1-mediated disease development.     

Leukemogenesis of Adult T-Cell Leukemia

Adult T-cell leukemia (ATL) is one of the most aggressive hematologic malignancies and is caused by human T-cell leukemia virus type I (HTLV-I). Tax, encoded by the HTLV-I pX region, has been recognized by its pleiotropic actions as a critical accessory protein playing a central role in leukemogenesis. However, fresh ATL cells frequently lose Tax protein expression via several mechanisms, such as genetic and epigenetic changes in the provirus. Furthermore, there is a long latency period before the onset of ATL, indicating the multistep mechanisms of leukemogenesis. Therefore, additional factors, including other viral proteins, genetic and epigenetic changes of the host genome, and alterations in the gene expression and immune systems of the host cells, may be implicated in ATL leukemogenesis. This review summarizes recent advances in the understanding of ATL leukemogenesis.     

Expression of Human Tumor-Associated Antigen RCAS1 in Adult T-Cell Leukemia/Lymphoma

In human cancer, RCAS1 (the receptor-binding cancer antigen expressed on SiSo cells) on the surface of various kinds of tumor cells reportedly induces the apoptosis of T-cells and natural killer cells, resulting in evasion of the immune system. In the present study, an immunohistochemical analysis of RCAS1 expression was performed with lymph node specimens obtained from patients with adult T-cell leukemia/lymphoma (ATLL). Positive staining was seen in 15 (75%) of 20 cases and in all cases of patients with short survival times. In the cases of B-cell lymphomas, positive staining was seen in only 1 (13%) of 8 cases. These findings indicate that expression of RCAS1 may be associated with the evasion from immune surveillance of cells infected with human T-lymphotropic virus type I, resulting in the development of overt leukemia/lymphoma. Determination of RCAS1 expression may be useful for predicting the prognosis of patients with ATLL.     

In vitro basal T-cell proliferation among asymptomatic Human T cell Leukemia Virus type 1 patients co-infected with hepatitis C and/or Human Immunodeficiency Virus type 1

Background

Infection with Human T cell Leukemia Virus type 1 can be associated with myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory diseases. Lymphocytes from about half of Human T cell Leukemia Virus type 1-infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease and viral burden is poorly understood.

Detection of<Emphasis Type="Italic">NOTCH1</Emphasis> Mutations in Adult T-cell Leukemia/Lymphoma and Peripheral T-Cell Lymphoma

We analyzed NOTCH1 gene mutation in 53 adults with mature T-cell leukemia/lymphoma: 21 patients with adult T-cell leukemia (ATL), 25 with T-cell non-Hodgkin's lymphoma (T-NHL), and 7 with T-cell prolymphocytic leukemia. We detected a nonsense mutation, C7249T (resulting in Q2417X, where X is a termination codon) in the PEST domain of NOTCH1 in an ATL patient and detected a 3-bp deletion (positions 7234-7236) that resulted in deletion of a proline codon at codon 2412 in the PEST domain of NOTCH1 in a patient with a T-NHL, peripheral T-cell lymphoma-unspecified (PTCL-u). We also analyzed the expression of NOTCH1 target genes (HES1, CCND1, and MYC), all of which were expressed in the sample of the PTCL-u patient with the NOTCH1 mutation, but found only MYC to be expressed in the sample from the ATL patient. These findings suggest that nonsense mutation in the PEST domain in the ATL case was associated with NOTCH1 signaling through a pathway different from that for T-cell acute lymphoblastic leukemia (T-ALL). Although NOTCH1 mutation occurs infrequently in mature T-cell leukemia/lymphoma, NOTCH1 may be involved in leukemogenesis associated with various forms of T-cell leukemia/lymphoma rather than only with T-ALL.     

Two Cases of Secondary Acute Myeloid Leukemia Accompanying Adult T-Cell Leukemia/Lymphoma

We identified 2 cases of secondary acute myeloid leukemia (AML) following adult T-cell leukemia/lymphoma (ATL) in patients who had previously received chemotherapy. Both cases were thought to represent therapy-related AML because the patients had previously received combination chemotherapy including epipodophyllotoxin, anthracycline, and alkylating agents for the ATL. The cases were diagnosed as AML M4 with eosinophilia and AML M2, with the chromosomal abnormalities inv(16)(p13q22) and t(8;21)(q22;q22), respectively. In our hospital, only these 2 cases of secondary AML accompanying ATL were identified among 90 cases of acute- or lymphoma-type ATL diagnosed from October 1999 to July 2006. The frequency of coexisting AML and ATL is lower than that reported for acute leukemia coexisting with other lymphoid malignancies. The low frequency of secondary leukemia with ATL may be associated with the short survival times of ATL patients.     

Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis

Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2.     

Mixed connective tissue disease with interstitial pneumonia in HTLV-1 carrier: case report and review of the literature

We report on a carrier of human T-lymphotropic virus type 1 (HTLV-1) who developed mixed connective tissue disease (MCTD). This patient suddenly manifested clinical symptoms and interstitial pneumonia ascribable to MCTD following long-term infection with HTLV-1. After initiation of oral prednisolone all manifestations quickly improved in parallel with a decrease in inflammatory reactions. In this patient HTLV-1 infection might have played an important role in the pathogenesis of MCTD. Since HTLV-1 can cause adult T-cell leukemia and HTLV-1-associated myelopathy, and also collagen diseases including MCTD, careful observation is necessary even in a carrier, particularly when autoantibodies are detectable in serum.     

Research and discovery of the first human cancer virus, HTLV-1

Human T-cell lymphoma virus (HTLV)-1 was the first human retrovirus to be discovered. It has been recognized as the cause of adult T-cell leukemia (ATL). In addition to giving a historical perspective on HTLV-1 and other retrovirus research, this paper discusses the origin of HTLV-1; the modes of transmission and global epidemiology of HTLV-1 infection; the genome of HTLV-1 and the mechanism of HTLV-1-induced leukemogenesis; the role of HTLV-1 in other diseases, and recent breakthroughs in ATL therapy.     

Human T-Lymphotropic Virus Type 1 (HTLV-1): Persistence and Immune Control

The human retrovirus human T-lymphotropic virus type 1 (HTLV-1) is associated with two distinct types of disease: the malignancy known as adult T-cell leukemia and a range of chronic inflammatory conditions including the central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Until recently, it was believed that HTLV-1 was largely latent in vivo. However, evidence from a number of types of experiments shows that HTLV-1 persistently expresses its genes, and that the "set point" of an individual's proviral load of HTLV-1 is mainly determined by the efficiency of that individual's cellular immune response to the virus. These conclusions have two main consequences. First, HTLV-1 may be vulnerable to antiretroviral drug therapy or immunotherapy. Second, HTLV-1 infection has become a useful system to analyze the determinants of the efficiency of the antiviral immune response.     

Revisiting Keratoconjunctivitis sicca associated with Human T-Cell Lymphotropic Virus Type 1: prevalence,clinical aspects and proviral load

BackgroundThe prevalence of keratoconjunctivitis sicca (KCS) associated with Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) (HTLV-1/KCS) has been estimated at around 37%, but its clinical manifestations are poorly described.PurposeTo determine the prevalence and associated factors of HTLV-1/KCS in a large cohort of HTLV-1-infected individuals living in Salvador, Brazil.MethodsA cross-sectional study was conducted between June 2004 and September 2017 at the Integrative and Multidisciplinary Center for HTLV in Salvador, Bahia-Brazil. Data from 758 HTLV-1-infected patients was collected. A complete ophthalmologic examination was performed in both eyes. Lacrimal function was evaluated by breakup time, Rose Bengal and Schirmer I Tests. KCS diagnosis was considered in the presence of at least two out of three positive tests. HTLV-1 proviral load Crude and Adjusted Prevalence Rates (PR) with 95% Confidence Intervals (95% CI) were estimated using multivariate Poisson Regression with robust error variance.ResultsThe overall prevalence of KCS was 31.7%, with higher rates observed in HTLV-1-associated myelopathy/tropical spastic paraparesis patients (crude PR: 1.84; CI95%: 1.50–2.26) even after adjusting for age, sex, time of HTLV-1 diagnosis and schooling (adjusted PR: 1.63; CI95%: 1.31–2.02). Proviral load, low corrected visual acuity, burning and/or pain and itching were all significantly higher in patients with KCS.ConclusionBurning and/or pain and itching and low corrected visual acuity were the most common alterations of HTLV-1/KCS. High Proviral load was found to be associated with the presence of KCS. It is strongly recommended that HTLV-1 patients undergo periodic ophthalmologic examination to promote the early diagnosis of KCS and prevent the consequences associated with dry eye disease.     

Factors associated with pain in individuals infected by human T-cell lymphotropic virus type 1 (HTLV-1)

Introduction

Despite the high prevalence of chronic pain in individuals infected with HTLV-1, predictive and protective factors for its development are still unclear.

HTLV-1, Immune Response and Autoimmunity

Human T-lymphotropic virus type-1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATL). Tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM) is involved in the development of autoimmune diseases including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Sjögren’s Syndrome (SS). The development of HTLV-1-driven autoimmunity is hypothesized to rely on molecular mimicry, because virus-like particles can trigger an inflammatory response. However, HTLV-1 modifies the behavior of CD4⁺ T cells on infection and alters their cytokine production. A previous study showed that in patients infected with HTLV-1, the activity of regulatory CD4⁺ T cells and their consequent expression of inflammatory and anti-inflammatory cytokines are altered. In this review, we discuss the mechanisms underlying changes in cytokine release leading to the loss of tolerance and development of autoimmunity.