HTLV-1-associated Myelopathy/tropical Spastic Paraparesis Research Articles

HTLV Deregulation of the NF-κB Pathway: An Update on Tax and Antisense Proteins Role.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL), an aggressive CD4+/CD25+ T-cell malignancy and of a severe neurodegenerative disease, HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The chronic activation or deregulation of the canonical and non-canonical nuclear factor kappa B (NF-κB) pathways play a crucial role in tumorigenesis. The HTLV-1 Tax-1 oncoprotein is a potent activator of the NF-κB transcription factors and the NF-κB response is required for promoting the development of HTLV-1 transformed cell lines. The homologous retrovirus HTLV-2, which also expresses a Tax-2 transforming protein, is not associated with ATL. In this review, we provide an updated synopsis of the role of Tax-1 in the deregulation of the NF-κB pathway, highlighting the differences with the homologous Tax-2. Special emphasis is directed toward the understanding of the molecular mechanisms involved in NF-κB activation resulting from Tax interaction with host factors affecting several cellular processes, such as cell cycle, apoptosis, senescence, cell proliferation, autophagy, and post-translational modifications. We also discuss the current knowledge on the role of the antisense viral protein HBZ in down-regulating the NF-κB activation induced by Tax, and its implication in cellular senescence. In addition, we review the recent studies on the mechanism of HBZ-mediated inhibition of NF-κB activity as compared to that exerted by the HTLV-2 antisense protein, APH-2. Finally, we discuss recent advances aimed at understanding the role exerted in the development of ATL by the perturbation of NF-κB pathway by viral regulatory proteins.

A Phase I–IIA Study of Mogamulizumab for HTLV-1–Associated Myelopathy

Human T-lymphotropic virus type 1 (HTLV-1) causes HTLV-1–associated myelopathy–tropical spastic paraparesis (HAM–TSP). HAM–TSP presents with

Human T-lymphotropic virus 1 (HTLV-1) pathogenesis: A systems virology study.

The main mechanisms of interaction between Human T-lymphotropic virus type 1 (HTLV-1) and its hosts in the manifestation of the related disease including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL) are yet to be determined. It is pivotal to find out the changes in the genes expression toward an asymptomatic or symptomatic states. To this end, the systems virology analysis was performed. Firstly, the differentially expressed genes (DEGs) were taken pairwise among the four sample sets of Normal, Asymptomatic Carriers (ACs), ATLL, and HAM/TSP. Afterwards, the protein-protein interaction networks were reconstructed utilizing the hub genes. In conclusion, the pathways of cells proliferation and transformation were identified in the ACs state. In addition to immune pathways in ATLL, the inflammation and cancer pathways were discened in both diseases of ATLL and HAM/TSP. The outcomes can specify the genes involved in the pathogenesis and help to design the drugs in the future.

Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP.

Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. Understanding the interaction between host and HTLV-1 and the molecular mechanisms associated with disease pathogenesis is critical for development efficient therapies. Two HTLV-1 genes, tax and HTLV-1 basic leucine zipper factor (HBZ), have been demonstrated to play important roles in HTLV-1 infectivity and the growth and survival of leukemic cells. Increased HTLV-1 Tax expression induces the expression of various cellular genes such as IL-2 and IL-15, which directly contributes to lymphocyte activation and immunopathogenesis in HAM/TSP patients. However, little is known about the molecular and cellular mechanism of HBZ in development of HAM/TSP. It has been reported that HBZ mRNA expression was detected in HAM/TSP patients higher than in asymptomatic carriers and correlated with proviral load and disease severity. Unlike HTLV-1 tax, HBZ escapes efficient anti-viral immune responses and therefore these reactivities are difficult to detect. Thus, it is important to focus on understanding the function and the role of HTLV-1 tax and HBZ in disease development of HAM/TSP and discuss the potential use of these HTLV-1 viral gene products as biomarkers and therapeutic targets for HAM/TSP.

Using a new tool to evaluate the functional capacity of patients with HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP)

HAM/TSP patients experience impaired functional capacity. The use of categorical scales to accurately describe motor ability in these patients has been questioned.Aim: To evaluate the functional capacity of HAM/TSP patients by using the individual tests comprising the GDLAM protocol.Methods: Cross sectional study carried out in the CHTLV, Salvador, Brazil. Functional capacity was evaluated using the tests of the GDLAM protocol (timed 10-minute walk, getting up from a sitting position, rising from a prone position, getting up from a chair, and moving around the house). Functional classifications were made by comparing patient performance to that of uninfected control individuals.Results: Twenty-four HAM/TSP and 25 healthy individuals were enrolled. Only 75% HAM/TSP patients completed the GDLAM protocol. Six patients failed to perform the RPP test. Timed measurements were significantly higher in the HAM/TSP patients in comparison to uninfected controls.Conclusion: The use of alternative methods, such as the individual tests comprising the GDLAM protocol, may more accurately assess motor function in HAM/TSP patients.

A comparative study of human T-cell lymphotropic virus-associated myelopathy in HIV-positive and HIV-negative patients in KwaZulu-Natal

Background: KwaZulu-Natal is an endemic area for HIV and human T-cell lymphotropic virus (HTLV) infection. The main neurological manifestation of HTLV is HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The effect of HIV co-infection in patients with HAM/TSP is not well documented.Aims: To determine the prevalence of HIV seropositivity in patients with HAM/TSP and compare the clinical, laboratory and radiological features of patients mono-infected with HTLV and those dually infected with HTLV and HIV.Methods: Adult patients referred to the Neurology Department at Inkosi Albert Luthuli Central Hospital in KwaZulu-Natal, South Africa, for the period 01 January 2004 to 31 December 2015 with a positive HTLV serology were identified from the National Health Laboratory Service database. A retrospective chart review was conducted to identify all patients who had a diagnosis of HAM/TSP and to record their HIV status. Clinical, laboratory and radiological data were compared for HIV-positive and HIV-negative patients.Results: A total of 52 patients with HAM/TSP were identified. HIV results were available in 44 patients of whom 23 (52%) patients were HIV co-infected. Patients who were HIV-positive had a younger age of presentation compared to HIV-negative patients (median: 31 vs 50 years, p = 0.002). HIV-positive patients had a median duration of symptoms at presentation of 12 months compared to 16 months for HIV-negative patients, but the difference did not reach statistical significance (p = 0.082). The CD4 cell counts of HIV-positive patients were well preserved with a median count of 781 cells/µL.Conclusions: HIV co-infection is commonly seen in the setting of HAM/TSP in KwaZulu-Natal. An interaction between the viruses may accelerate the development of HAM/TSP, leading to a younger age of presentation. Co-infection may have treatment implications because of CD4 counts being preserved in these patients.

The CC chemokine ligand (CCL) 1, upregulated by the viral transactivator Tax, can be downregulated by minocycline: possible implications for long-term treatment of HTLV-1-associated myelopathy/tropical spastic paraparesis

BackgroundChemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/ macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).ResultsThe results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines.ConclusionsThe present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression.

Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo.

Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+CCR4+ effector/memory T cells in vivo. However, it remains unknown whether HTLV-1 preferentially infects these T cells or this virus converts infected precursor cells to specialized T cells. Expression of viral genes in vivo is critical to study viral replication and proliferation of infected cells. Therefore, we first analyzed viral gene expression in non-human primates naturally infected with simian T-cell leukemia virus type 1 (STLV-1), whose virological attributes closely resemble those of HTLV-1. Although the tax transcript was detected only in certain tissues, Tax expression was much higher in the bone marrow, indicating the possibility of de novo infection. Furthermore, Tax expression of non-T cells was suspected in bone marrow. These data suggest that HTLV-1 infects hematopoietic cells in the bone marrow. To explore the possibility that HTLV-1 infects hematopoietic stem cells (HSCs), we analyzed integration sites of HTLV-1 provirus in various lineages of hematopoietic cells in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a HTLV-1 carrier using the high-throughput sequencing method. Identical integration sites were detected in neutrophils, monocytes, B cells, CD8+ T cells and CD4+ T cells, indicating that HTLV-1 infects HSCs in vivo. We also detected Tax protein in myeloperoxidase positive neutrophils. Furthermore, dendritic cells differentiated from HTLV-1 infected monocytes caused de novo infection to T cells, indicating that infected monocytes are implicated in viral spreading in vivo. Certain integration sites were re-detected in neutrophils from HAM/TSP patients at different time points, indicating that infected HSCs persist and differentiate in vivo. This study demonstrates that HTLV-1 infects HSCs, and infected stem cells differentiate into diverse cell lineages. These data indicate that infection of HSCs can contribute to the persistence and spread of HTLV-1 in vivo.

CT Chest and pulmonary functional changes in patients with HTLV-associated myelopathy in the Eastern Brazilian Amazon.

The aim of this study was to compare computed tomography (CT) scans of chest and lung function among patients with Human T-Lymphotropic Virus Type 1 (HTLV) with and without HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In this cross-sectional study performed between January 2013 and June 2016, we included 48 patients with HAM/TSP (19 women and 11 men) and without HAM/TSP (12 women and 6 men). We compared CT findings and lung functions of these groups. Patients who had HAM/TSP had abnormal CT findings (P = 0.000), including more frequent bronchiectasis (P = 0.049), parenchymal bands (P = 0.007), interlobular septal thickening (P = 0.035), and pleural thickening (P = 0.009). In addition, neither patients with HAM/TSP (9/30; 30%) nor the controls (0/18; 0%) had obstructive or restrictive lung disease (P = 0.009). HTLV diagnosis should be considered in all patients with abnormal CT findings in whom no other cause is apparent. It is important to remember that lung disease increases the rates of morbidity and mortality in developing countries.

Imaging spinal cord atrophy in progressive myelopathies: HTLV-I-associated neurological disease (HAM/TSP) and multiple sclerosis (MS).

Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. All spinal cord regions are thinner in HAM/TSP (56 mm2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8+ T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719-728.

Retinal Nerve Fiber Layer Thickness in Human T-cell Lymphotropic Virus Type 1 Patients

ABSTRACTPurpose: To determine whether there is an optic neuropathy (ON) in patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection.Methods: We included HTLV-1 asymptomatic carriers (a.c.HTLV-1) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) patients between January 1st, 2014 and March 31st, 2015. All patients had complete eye examination. The visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness were measured and compared to age- and sex-matched control groups including patients seen in our refraction clinic with no previous medical or surgical history.Results: Thirty-one a.c.HTLV-1 (group 1) and 29 TSP/HAM patients (group 2) were included. The average RNFL thickness was 99.9 ± 14.3 µm in group 1 and 87.8 ± 19.2 µm in group 2. The average RFNL thicknesses were lower in both groups, when compared to controls. The difference was significant in patients with TSP/HAM (87.8 ± 19.2 µm vs. 97 ± 7.8 µm; p = 0.003) who also had significantly decreased VA.Conclusions: We report here the first study about the RNFL thickness in patients with TSP/HAM. In these patients, there is decrease of the RNFL thickness with subtle but definite decrease of VA. This suggests that subclinical ON occurs in the natural history of the disease. The diagnosis of TSP/HAM must be evoked as a differential of primary progressive multiple sclerosis in a population at risk. Moreover, RNFL thinning with no evidence of glaucoma should raise suspicion for HTLV-1 infection and TSP/HAM in a population at risk.

Shrinking spinal cord in anterior-posterior direction in HAM/TSP

Background: HTLV-1 is thought to be infected with 10-20 million people worldwide, and a few of them develop into HTLV-1 associated myelopathy/ Tropical spastic paraparesis (HAM/TSP). There are several reports on spinal cord morphologic change in HAM/TSP. In the observation of the cross section, spinal cord seemed to be flattened due to atrophy in the anterioposterior direction.

HTLV-1 intrafamilial transmission among Japanese immigrants in Brazil.

Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The aim of this study was to investigate the intrafamilial transmission of HTLV-1 among Japanese immigrants and their descendants living in a non-endemic area of central Brazil. Six families were investigated. Thirty-seven relatives of the six index cases were tested by ELISA for the presence of anti-HTLV antibodies, and the positive cases were confirmed by Western blot. HTLV-1 isolates were genotyped by partial nucleotide sequencing (5' LTR) of the proviral DNA. All individuals, including index cases and relatives, were asymptomatic. In five families, at least one relative was infected with HTLV-1. In all, eight (22%) relatives (one mother, four wives, one brother, and two brothers-in-law) were infected. However, none of the 22 individuals under 55 years of age was infected. In each family, the HTLV-1 sequences from the relatives were identical or almost identical to that of the index case, except in one case. Pedigrees of the families, together with socio-demographic data of the HTLV-1 infected individuals, strongly suggested the occurrence of both vertical and sexual transmission, with breastfeeding as an important risk factor. Whether and why the virus transmission is less effective among younger generations deserves to be further investigated.

IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways.

Human T-cell leukemia virus type-1 (HTLV-1) causes two distinct diseases, adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since there are no disease-specific differences among HTLV-1 strains, the etiological mechanisms separating these respective lymphoproliferative and inflammatory diseases are not well understood. In this study, by using IL-2-dependent HTLV-1-infected T-cell lines (ILTs) established from patients with ATL and HAM/TSP, we demonstrate that the anti-inflammatory cytokine IL-10 and its downstream signals potentially act as a switch for proliferation in HTLV-1-infected cells. Among six ILTs used, ILTs derived from all three ATL patients grew much faster than those from three HAM/TSP patients. Although most of the ILTs tested produced IFN-γ and IL-6, the production of IL-10 was preferentially observed in the rapid-growing ILTs. Interestingly, treatment with exogenous IL-10 markedly enhanced proliferation of the slow-growing HAM/TSP-derived ILTs. The IL-10-mediated proliferation of these ILTs was associated with phosphorylation of STAT3 and induction of survivin and IRF4, all of which are characteristics of ATL cells. Knockdown of STAT3 reduced expression of IL-10, implying a positive-feedback regulation between STAT3 and IL-10. STAT3 knockdown also reduced survivin and IRF4 in the IL-10- producing or IL-10- treated ILTs. IRF4 knockdown further suppressed survivin expression and the cell growth in these ILTs. These findings indicate that the IL-10-mediated signals promote cell proliferation in HTLV-1-infected cells through the STAT3 and IRF4 pathways. Our results imply that, although HTLV-1 infection alone may not be sufficient for cell proliferation, IL-10 and its signaling pathways within the infected cell itself and/or its surrounding microenvironment may play a critical role in pushing HTLV-1-infected cells towards proliferation at the early stages of HTLV-1 leukemogenesis. This study provides useful information for understanding of disease mechanisms and disease-prophylactic strategies in HTLV-1 infection.

Spinal cord anteroposterior atrophy in HAM/TSP: Magnetic resonance imaging and neuropathological analyses

To evaluate the spinal cord atrophy that occurs in HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP), we conducted magnetic resonance imaging (MRI) and pathological analyses. In the MRI study, 15 patients with HAM/TSP and 20 age-matched normal control subjects were enrolled. Anteroposterior and transverse distances and cross-sectional areas were measured and calculated at the C2, C4, C6, T2, and T6 vertebral levels. In the pathological study, spinal cord autopsy specimens were compared between a HAM/TSP case and an adult T cell leukemia/lymphoma case. In both the MRI and pathological studies, HAM/TSP spinal cords demonstrated more severe atrophy in the anteroposterior direction than those of controls. The spinal cord atrophy and pathological changes in HAM/TSP occurred predominantly in the white matter, especially in the lateral columns. This is the first report indicating spinal cord atrophy in the anteroposterior direction using MRI. In pathological analysis, atrophy and pathological changes were prominent in areas of the spinal cord with slow blood flow. Hemodynamic and anatomical factors are speculated to be among the main mechanisms of atrophy in the anteroposterior direction.

HTLV-1-infected thymic epithelial cells convey the virus to CD4+ T lymphocytes

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4+T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell–cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4+ T cell line and to CD4+ T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4+ T lymphocytes, which in turn will cause disease in the periphery.

The Duffy null genotype is associated with a lower level of CCL2, leukocytes and neutrophil count but not with the clinical outcome of HTLV-1 infection.

Purpose. Chemokines are important in the immune response against viral infections, and may play a role in human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis. Polymorphisms in the Duffy antigen receptor for chemokines (DARC), such as rs12075 (A>G; FY*B>FY*A) and rs281477 (-46T>C; GATA-1 box) may influence circulating concentrations of proinflammatory chemokines. We investigate whether Duffy genotypes influence the HTLV-1 proviral load (PVL) level, HTLV-1 infection outcome and chemokine concentrations in HTLV-1 asymptomatic carriers (AC=162), HAM/TSP patients (HAM=135) and seronegative individuals (SN=71).Methodology. Quantification of plasmatic IL8, CCL2 and CCL5 were performed by flow cytometry and Duffy genotypes were investigated by real-time PCR. HTLV-1 PVL was quantified in peripheral blood. To control for spurious association, individual ancestry profiles in AC and HAM groups were investigated.Results/Key findings. PVL and IL8 level were significantly higher in the HAM group than in the AC group, but were not associated with Duffy genotypes. The highest CCL2 and CCL5 levels were seen in the SN group, and there was no difference when comparing the infected groups. The level of CCL5 was not associated with Duffy genotypes. The polymorphism -46 C/C that abrogates the DARC expression on the erythrocytes was significantly associated with lower levels of CCL2, neutrophil and white blood cell (WBC) counts in HTLV-1-infected individuals.Conclusion. We conclude that although the Duffy null genotype was associated with leukopenia, neutropenia and lower levels of CCL2, the data do not suggest the influence of Duffy genotypes on the neurologic outcome of HTLV-1 infection, but may be a confounding factor in comparison HTLV-1-infected populations with different ancestries, especially when defining inflammatory biomarkers.

Polymorphic Nature of Human T-Cell Leukemia Virus Type 1 Particle Cores as Revealed through Characterization of a Chronically Infected Cell Line

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 cell-to-cell transmission is dependent on the release of infectious virus particles into the virological synapse. The HTLV-1 particle structure is still poorly understood, and previous studies analyzed viruses produced by transformed lymphocytic cell lines chronically infected with HTLV-1, particularly the MT-2 cell line, which harbors truncated proviruses and expresses aberrant forms of the Gag protein. In this study, we demonstrate that the chronically infected SP cell line harbors a relatively low number of proviruses, making it a more promising experimental system for the study of the HTLV-1 particle structure. We first identified the genomic sites of integration and characterized the genetic structure of the gag region in each provirus. We also determined that despite encoding a truncated Gag protein, only the full-length Gag protein was incorporated into virus particles. Cryo-transmission electron microscopy analyses of the purified virus particles revealed three classes of particles based upon capsid core morphology: complete cores, incomplete cores, and particles without distinct electron densities that would correlate with the capsid region of a core structure. Observed cores were generally polygonal, and virus particles were on average 115 nm in diameter. These data corroborate particle morphologies previously observed for MT-2 cells and provide evidence that the known poor infectivity of HTLV-1 particles may correlate with HTLV-1 particle populations containing few virus particles possessing a complete capsid core structure.IMPORTANCE Studies of retroviral particle core morphology have demonstrated a correlation between capsid core stability and the relative infectivity of the virus. In this study, we used cryo-transmission electron microscopy to demonstrate that HTLV-1 particles produced from a distinct chronically infected cell line are polymorphic in nature, with many particles lacking organized electron densities that would correlate with a complete core structure. These findings have important implications for infectious HTLV-1 spread, particularly in the context of cell-to-cell transmission, a critical step in HTLV-1 transmission and pathogenesis.

Mediators Go Together: High Production of CXCL9, CXCL10, IFN-γ, and TNF-α in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic demyelinating and disabling syndrome caused by human T lymphotropic virus 1 (HTLV-1). Although the pathogenic mechanisms that lead to HAM/TSP outcome have not been elucidated, genetic and immunological factors may be involved in the myelopathy occurrence. This study aimed to compare cytokines, chemokines, and nitric oxide (NO) levels in asymptomatic and HAM/TSP HTLV-1-infected patients. The study group consisted of 21 HAM/TSP and 48 asymptomatic HTLV-1 patients. Chemokines (CCL5, CCL2, CXCL8, CXCL9, and CXCL10) and cytokines [IL-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-4, IL-6, and IL-10] were measured using cytometric bead array, whereas NO production was measured after reaction of supernatants with nitrate reduction solution. CXCL9 and CXCL10 chemokines levels were found to be higher in the HAM/TSP group. CXCL9 was also strongly correlated with CXCL10 and both CXCL9 and CXCL10 were moderately correlated with CCL2 and CCL5 levels, in both HAM/TSP and asymptomatic groups. There was no significant difference related to NO, IL-4, IL-6, and IL-10 levels between the clinical groups but TNF-α and IFN-γ levels were increased in HAM/TSP patients. Thus, factors such as CXCL9, CXCL10, TNF-α, and IFN-γ could be good prognostic biomarker candidates, and further studies may help to clarify their association with HAM/TSP immunopathogenesis.

Systemic diseases in patients with HTLV-1-associated uveitis

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) carriers may develop severe systemic diseases, such as adult T cell leukaemia (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This study aims to investigate...