Establishment of a novel human T-cell leukemia virus type 1 infection model using cell-free virus.

The primary mode of infection by human T-cell leukemia virus type 1 (HTLV-1) is cell-to-cell transmission during contact between infected cells and target cells. Cell-free HTLV-1 infections are known to be less efficient than infections with other retroviruses, and transmission of free HTLV-1 is considered not to occur in vivo. However, it has been demonstrated that cell-free HTLV-1 virions can infect primary lymphocytes and dendritic cells in vitro, and that virions embedded in biofilms on cell membranes can contribute to transmission. The establishment of an efficient cell-free HTLV-1 infection model would be a useful tool for analyzing the replication process of HTLV-1 and the clonal expansion of infected cells. We first succeeded in obtaining supernatants with high-titer cell-free HTLV-1 using a highly efficient virus-producing cell line. The HTLV-1 virions retained the structural characteristics of retroviruses. Using this cell-free infection model, we confirmed that a variety of cell lines and primary cultured cells can be infected with HTLV-1 and demonstrated that the provirus was randomly integrated into all chromosomes in the target cells. The provirus-integrated cell lines were HTLV-1-productive. Furthermore, we demonstrated for the first time that cell-free HTLV-1 is infectious in vivo using a humanized mouse model. These results indicate that this cell-free infection model recapitulates the HTLV-1 life cycle, including entry, reverse transcription, integration into the host genome, viral replication, and secondary infection. The new cell-free HTLV-1 infection model is promising as a practical resource for studying HTLV-1 infection.IMPORTANCECo-culture of infected and target cells is frequently used for studying HTLV-1 infection. Although this method efficiently infects HTLV-1, the cell mixture is complex, and it is extremely difficult to distinguish donor infected cells from target cells. In contrast, cell-free HTLV-1 infection models allow for more strict experimental conditions. In this study, we established a novel and efficient cell-free HTLV-1 infection model. Using this model, we successfully evaluated the infectivity titers of cell-free HTLV-1 as proviral loads (copies per 100 cells) in various cell lines, primary cultured cells, and a humanized mouse model. Interestingly, the HTLV-1-associated viral biofilms played an important role in enhancing the infectivity of the cell-free infection model. This cell-free HTLV-1 infection model reproduces the replication cycle of HTLV-1 and provides a simple, powerful, and alternative tool for researching HTLV-1 infection.

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. 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.

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.

HIV-1 and HTLV-1 Transmission Modes: Mechanisms and Importance for Virus Spread.

So far, only two retroviruses, human immunodeficiency virus (HIV) (type 1 and 2) and human T-cell lymphotropic virus type 1 (HTLV-1), have been recognized as pathogenic for humans. Both viruses mainly infect CD4+ T lymphocytes. HIV replication induces the apoptosis of CD4 lymphocytes, leading to the development of acquired immunodeficiency syndrome (AIDS). After a long clinical latency period, HTLV-1 can transform lymphocytes, with subsequent uncontrolled proliferation and the manifestation of a disease called adult T-cell leukemia (ATLL). Certain infected patients develop neurological autoimmune disorder called HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (HAM/TSP). Both viruses are transmitted between individuals via blood transfusion, tissue/organ transplantation, breastfeeding, and sexual intercourse. Within the host, these viruses can spread utilizing either cell-free or cell-to-cell modes of transmission. In this review, we discuss the mechanisms and importance of each mode of transmission for the biology of HIV-1 and HTLV-1.

Comparison between various biosensor methods for human T-lymphotropic virus-1 (HTLV-1) detection.

Due to the drawback of traditional and current diagnostic methods including serological and molecular assays, the development of the rapid and free-PCR techniques can be an alternative technique for the human T-cell lymphotropic virus (HTLV-1) DNA detection sequences. On the other hand, early detection of HTLV-1 prevents two dangerous diseases including Adult T-cell leukemia/lymphoma and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis. The biosensor-based methods are sensitive techniques that can provide new opportunities to detect infectious diseases, particularly in the early stage. This study provides a comparative view among recently designed biosensors for the detection of HTLV-1.

Very high prevalence of infection with the human T cell leukaemia virus type 1c in remote Australian Aboriginal communities: Results of a large cross-sectional community survey.

Infection with the human T cell leukaemia virus type 1 (HTLV-1) subtype C is endemic among Aboriginal people in central Australia. To provide insights into the risk factors for transmission, we conducted the first large-scale, community-based prevalence study in seven remote Aboriginal communities. Residents >2 years old were invited to participate in the study between August 2014 and June 2018. HTLV-1 infection was defined as a positive western blot (WB) test or a positive HTLV-1 PCR. 720 community residents participated in the study (children <15 years, 142; adults, 578). Prevalences for children and adults were 3.5% (5/142) and 36.8% (213/578), respectively, reaching 49.3% (106/215) for those older than 45 years. A wide range of proviral loads were measured for both asymptomatic and symptomatic participants with no difference within groups according to age or gender; however, median PVL was 1.34 log10 higher for symptomatic participants. The adult prevalence of HTLV-1 infection in central Australia is the highest reported worldwide. Sexual contact is likely to be the predominant mode of transmission.

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a "contagium vivum fluidum", or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed "viruses", were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral "antisense" transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies.

Hypovitaminosis D Is Associated with Higher Levels of Inflammatory Cytokines and with HAM/TSP in HTLV-Infected Patients.

Recent studies have shown the effects of vitamin D on host response to infectious diseases. Some studies detected a high prevalence of hypovitaminosis D in HIV-infected patients, but scarce information exists for HTLV-1 infection. We conducted a cross-sectional study to evaluate the frequency of hypovitaminosis D in HTLV-1 patients and its relationship with their immune response in HTLV-infected patients and in age- and gender-matched controls at a Brazilian rehabilitation hospital. We compared vitamin D, interleukin-6 (IL-6), tumoral necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) levels across groups. Logistic regression was utilized to assess the association between hypovitaminosis D and cytokine levels. We enrolled 161 HTLV-infected subjects (129 HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 32 asymptomatic HTLV carriers) and equal number of HTLV-negative controls. We observed a significantly higher prevalence of hypovitaminosis D in patients with HAM/TSP than in HTLV asymptomatic carriers (p < 0.001), or controls (p < 0.001). HAM/TSP patients also had higher levels of IL-6 and IFN-γ than asymptomatic carriers. Patients with HAM/TSP and hypovitaminosis D had higher levels of TNF-α than asymptomatic HTLV carriers. These findings suggest hypovitaminosis D plays a role in HAM/TSP pathogenesis, and it needs to be evaluated in further studies.

Work-Related Human T-lymphotropic Virus 1 and 2 (HTLV-1/2) Infection: A Systematic Review.

Human T-lymphotropic virus 1 and 2 (HTLV-1/2) belong to the delta group of retroviruses which may cause a life-long infection in humans, HTLV-1 leading to adult T-cell leukemia/lymphoma and other diseases. Different transmission modes have been described, such as breastfeeding, and, as for other blood-borne pathogens, unsafe sexual activity, intravenous drug usage, and blood transfusion and transplantation. The present systematic review was conducted to identify all peer-reviewed studies concerning the work-related infection by HTLV-1/2. A literature search was conducted from January to May 2021, according to the PRISMA methodology, selecting 29 studies: seven related to health care workers (HCWs), five to non-HCWs, and 17 to sex workers (SWs). The findings showed no clear evidence as to the possibility of HTLV-1/2 occupational transmission in HCWs, according to the limited number and quality of the papers. Moreover, non-HCWs showed a higher prevalence in jobs consistent with a lower socioeconomic status or that could represent a familial cluster, and an increased risk of zoonotic transmission from STLV-1-infected non-human primates has been observed in African hunters. Finally, a general increase of HTLV-1 infection was observed in SWs, whereas only one paper described an increased prevalence for HTLV-2, supporting the urgent need for prevention and control measures, including screening, diagnosis, and treatment of HTLV-1/2, to be offered routinely as part of a comprehensive approach to decrease the impact of sexually transmitted diseases in SWs.

Case Report: HTLV-1-Induced Adult T-Cell Leukemia and Tropical Spastic Paresis.

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus endemic in many areas around the world. HTLV-1 can induce the development of adult T-cell leukemia (ATL) or myelopathy/tropical spastic paraparesis (HAM/TSP). We report a patient who presented to our outpatient clinic with massive splenomegaly, weight loss, urinary retention, and lower extremity weakness for the previous 3 years. The patient was found to have positive HTLV-1 by ELISA and Western blot from peripheral blood. Evaluation of the spleen demonstrated T-cell large granular lymphocyte leukemia consistent with ATL. In addition to progressive lower extremity weakness, hyperreflexia and clonus, cerebral spinal fluid was positive for HTLV-1 by ELISA and had a reversed CD4-to-CD8 ratio consistent with HAM/TSP. These findings suggest HTLV-1 induced ATL and HAM/TSP presenting simultaneously in the same patient.

Identification of joint gene players implicated in the pathogenesis of HTLV-1 and BLV through a comprehensive system biology analysis.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are oncogenic viruses that induce adult T cell leukemia/lymphoma (ATLL) and enzootic bovine leukosis (EBL), respectively. HTLV-1 principally infects CD4+ T cells comprising regulatory T cells (Tregs), T helper 1 (Th1), and T helper 2 (Th2), while BLV infects B lymphocytes. Both viruses may impel cell proliferation and malignancy. METHODS: To survey the transcriptomic variations due to HTLV-1 and BLV infection and further hematologic malignancies, differential expression genes (DEGs) were explored between leukemia and normal samples using the DESeq2 package. Gene set enrichment analyses (GSEA) were then performed to identify significant gene sets using the FGSEA package. Afterward, the protein-protein interaction (PPI) networks were reconstructed using the STRING online database. Eventually, the hub significant genes and modules were determined through network analysis and MCODE algorithm, respectively. RESULTS: Our results uncloaked that four common functional gene sets including mitotic-spindle, G2M-checkpoint, E2F-targets, and MYC-targets-V1 are involved in the human and ovine hosts. Furthermore, twelve up-regulated hub genes including BIRC5, CCNA2, CCNB2, BUB1, DLGAP5, TOP2A, PBK, ASPM, UBE2C, CEP55, KIF20A, and NUSAP1 were identified which were similarly activated in both human and ovine hosts. They mostly participate in pathways including cell cycle, cell division, DNA damage responses, growth factors production, and p53 signaling pathway. The dysregulated hub genes and pathways seem to be involved in the development and progression of the infected cells toward malignancy. CONCLUSION: There is common gene groups between HTLV-1 and BLV infections that promote viral malignancy through enhancing cell proliferation and overall survival of cancer cells. The dysregulated genes and pathways may be the efficient candidates for the therapy of the mentioned life-threatening diseases.

HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models.

Since the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative agent of the aggressive adult T-cell leukemia/lymphoma and inflammatory diseases such as the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cell models contribute to defining the role of HTLV proteins, as well as the mechanisms of cell-to-cell transmission of the virus. Otherwise, selected and engineered animal models are currently applied to recapitulate in vivo the HTLV-1 associated pathogenesis and to verify the effectiveness of viral therapy and host immune response. Here we review the current cell models for studying virus-host interaction, cellular restriction factors and cell pathway deregulation mediated by HTLV products. We recapitulate the most effective animal models applied to investigate the pathogenesis of HTLV-1-associated diseases such as transgenic and humanized mice, rabbit and monkey models. Finally, we summarize the studies on STLV and BLV, two closely related HTLV-1 viruses in animals. The most recent anticancer and HAM/TSP therapies are also discussed in view of the most reliable experimental models that may accelerate the translation from the experimental findings to effective therapies in infected patients.

The N93D mutation of the human T-cell leukemia virus type 1 envelope glycoprotein found in symptomatic patients enhances neuropilin-1 b1 domain binding.

Human T-cell leukemia virus type 1 (HTLV-1) infection of host cells is mainly mediated by interactions with the viral envelope glycoprotein surface unit (SU) and three host receptors: heparan sulfate proteoglycan, neuropilin-1 (Nrp1), and glucose transporter type 1. Residues 90-94 of SU are considered as a Nrp1 binding site, and our previous results show that an SU peptide consisting of residues 85-94 can bind directly to the Nrp1 b1 domain with a binding affinity of 7.4 µM. Therefore, the SU peptide is expected to be a good model to investigate the SU-Nrp1 interaction. Recently, the N93D mutation in the Nrp1 b1 binding region of the SU was identified in symptomatic patients with HTLV-1 infections in the Brazilian Amazon. However, it remains unclear how the SU-N93D mutation affects Nrp1 b1 binding. To elucidate the impact of the substituted Asp93 of SU on Nrp1 b1 binding, we analyzed the interaction between the SU-N93D peptide and Nrp1 b1 using isothermal titration calorimetry and nuclear magnetic resonance. The SU-N93D peptide binds directly to Nrp1 b1 with a binding affinity of 3.5 µM, which is approximately two-fold stronger than wild-type. This stronger binding is likely a result of the interaction between the substituted residue Asp93 of the N93D peptide and the four residues Trp301, Lys347, Glu348, and Thr349 of Nrp1 b1. Our results suggest that the interaction of SU Asp93 with the four residues of Nrp1 b1 renders the high affinity of the N93D mutant for Nrp1 b1 binding during HTLV-1 entry.

Tumorigenesis and diagnostic practice applied in two oncogenic viruses: Epstein Barr virus and T-cell lymphotropic virus-1-Mini review.

To date, seven viruses have been reliably connected to various forms of human cancer: Epstein Barr Virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), high-risk Human papillomavirus (HPV), Merkel Cell Polyomavirus (MCPV), Hepatitis B virus (HBV), hepatitis C virus (HCV), and Human T-cell leukemia virus type 1 (HTLV1). This mini-review summarizes two of these viruses, EPV and HTLV-1, in terms of their general pathway of infection, the key mechanism of cancer induction, and the prominent technologies used to detect the infections. EBV is the first discovered human oncovirus and HTLV - I is the first human retrovirus and both were discovered from patient with distinct lymphoma clinical condition. Both the viruses can immortalize lymphocytes invitro and lymphomas are common manifestation of majority oncogenic viruses. Lymphomagenesis are discovered in associated with EBV, HTLV-I, Human Immunodeficiency virus (HIV), Kaposi sarcoma - associated herpes virus and hepatitis c virus. Later the undefined mechanism behind the induction of cancer by these viruses was unveiled gradually along with the responsible cofactors and mimicry mechanism. These two viruses contrast in their genetic structure, location of the infection, and latency, yet clinically, they generate similar cancer disorders. The major focus of this study is to brief the mechanism of these two unrelated viral cancer promoting agents on how they simulate a condition similar to lymphoma which may or may not undergo mimicry and cofactor utilization process, handpicked and vital genes behind the transformation mechanism are given accordingly.

Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.

Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.

Prevalence of human T-lymphotropic virus type 1 and 2 (HTLV-1/-2) infection in pregnant women in Brazil: a systematic review and meta-analysis.

Human T-lymphotropic virus type 1 (HTLV-1) infection may cause serious disease, while pathogenicity of HTLV-2 is less certain. There are no screening or surveillance programs for HTLV-1/-2 infection in Brazil. By performing this systematic review, we aimed to estimate the prevalence of HTLV-1/-2 infections in pregnant women in Brazil. This review included cohort and cross-sectional studies that assessed the presence of either HTLV-1/-2 infection in pregnant women in Brazil. We searched BVS/LILACS, Cochrane Library/CENTRAL, EMBASE, PubMed/MEDLINE, Scopus, Web of Science and gray literature from inception to August 2020. We identified 246 records in total. Twenty-six of those were included in the qualitative synthesis, while 17 of them were included in the meta-analysis. The prevalence of HTLV-1 in Brazilian pregnant women, as diagnosed by a positive screening test and a subsequent positive confirmatory test, was 0.32% (95% CI 0.19-1.54), while of HTLV-2 was 0.04% (95% CI 0.02-0.08). Subgroup analysis by region showed the highest prevalence in the Northeast region (0.60%; 95% CI 0.37-0.97) for HTLV-1 and in the South region (0.16%; 95% CI 0.02-1.10) for HTLV-2. The prevalence of HTLV-1 is much higher than HTLV-2 infection in pregnant Brazilian women with important differences between regions. The prevalence of both HTLV-1/-2 are higher in the Northeast compared to Center-West region.

Risk factors for HTLV-1, acute kidney injury, and urinary tract infection among aboriginal adults with end stage kidney disease in central Australia.

Central Australia is a human T-cell leukemia virus type 1c (HTLV-1c) endemic region and has the highest incidence of chronic kidney disease (CKD) in Australia. The factors associated with HTLV-1 seropositivity among Aboriginal Australian adults with CKD receiving hemodialysis (HD) were determined. A retrospective observational study of Aboriginal adults (≥ 18 years) who were receiving regular HD at the two main dialysis units in Alice Springs, December 1, 2010 to December 31, 2015. Demographic and clinical data before commencing HD were extracted from hospital records from the first presentation to Alice Springs Hospital (ASH) to HD commencement and associations were determined using logistic regression. Among 373 patients receiving HD, 133 (35.9%) were HTLV-1 infected. Identifiable factors associated with HTLV-1 status included increasing age, male gender, and diabetes before HD. The odds of diabetes mellitus were significantly higher among patients with HTLV-1 (adjusted odds ratio [aOR]: 2.76, 95% confidence interval [CI]: 1.19, 6.39; p = 0.017). More than one-fifth of participants had an acute kidney injury, the risk of which was increased among those with a previous blood stream infection (aOR: 3.02, 95% CI: 1.71, 5.34, p < 0.001). Men with a high HTLV-1 proviral load (≥500 copies per 105 peripheral blood leukocytes) had an increased risk of urinary tract infection (UTI) before HD (aOR: 5.15, 95% CI: 1.62, 16.40; p = 0.006). A strong association between HTLV-1 and diabetes, and an increased risk of UTI among men with a high HTLV-1 PVL, suggest that interactions between HTLV-1 infection and conventional risk factors may increase the risk for CKD in this population.

Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.

HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10-9) and class II (P = 1.21 × 10-8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10-5), HLA-B*07:02 (P = 4.97 × 10-10), HLA-DRB1*01:01 (P = 1.15 × 10-9) and HLA-DQB1*05:01 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10-5), HLA-DRB1*15:01 (P = 1.06 × 10-5) and HLA-DQB1*06:02 (P = 1.78 × 10-6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10-10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

Comprehensive genomic analysis identifying heterogeneity in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are common in Japan. ATLL is an incurable T-cell malignancy induced by human T-cell lymphotropic virus type 1 (HTLV-1). The global genomics of ATLL can be summarized as alterations involving T-cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral-mediated T-cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV-1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL-related genes is identified in a part of HTLV-1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL-NOS is a heterogeneous disease type of T-cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL-NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.