Novel insights into human T-lymphotropic virus type-1 (HTLV-1) pathogenesis-host interactions in the manifestation of HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T-lymphotropic virus type-1 (HTLV-1) was the first discovered human oncogenic retrovirus, the etiological agent of two serious diseases have been identified as adult T-cell leukaemia/lymphoma malignancy and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a debilitating chronic neuro-myelopathy. Despite more than 40 years of molecular, histopathological and immunological studies on HTLV-1-associated diseases, the virulence and pathogenicity of this virus are yet to be clarified. The reason why the majority of HTLV-1-infected individuals (∼95%) remain asymptomatic carriers is still unclear. The deterioration of the immune system towards oncogenicity and autoimmunity makes HTLV-1 a natural probe for the study of malignancy and neuro-inflammatory diseases. Additionally, its slow worldwide spreading has prompted public health authorities and researchers, as urged by the WHO, to focus on eradicating HTLV-1. In contrast, neither an effective therapy nor a protective vaccine has been introduced. This comprehensive review focused on the most relevant studies of the neuro-inflammatory propensity of HTLV-1-induced HAM/TSP. Such an emphasis on the virus-host interactions in the HAM/TSP pathogenesis will be critically discussed epigenetically. The findings may shed light on future research venues in designing and developing proper HTLV-1 therapeutics.

Role of Interleukin-17 cytokine family in human T-cell lymphotropic virus type 1 (HTLV-1) infection and associated diseases.

BACKGROUND: Human T-lymphotropic virus (HTLV-1) is a neglected virus with worldwide distribution of over 10 million people and is the cause of two main associated diseases Adult T cell Leukemia-Lymphoma (ATLL), and HTLV-1-associated Myelopathy/Tropical Spastic paraparesis (HAM/TSP). The IL-17 cytokine family plays a crucial role in the host immunity against HTLV-1 and the development of associated disease. A systematic review was conducted to analyze all research reporting on the levels or expression of the IL-17 HTLV-1 infection and associated diseases. METHODS: The literature search was conducted in electronic databases including PubMed/Medline and Web of Sciences until January 31st, 2024, followed by the PRISMA guidelines. RESULTS: Our search revealed 20 eligible articles to be included in our study. The total number of cases studied was 1420, of which 386 were carriers without any symptoms, and were 176 ATLL and 237 HAM/TSP. The IL-17 cytokine family production or mRNA expression was higher in HAM/TSP patients but showed a trend toward reduction in the case of ATLL. CONCLUSIONS: Our results showed that while The IL-17 cytokine family plays a significant role in the immunopathogenesis of disease and clinical status of patients with inflammatory disorders such as HAM/TSP, IL-17 production is diminished and the RORC/IL-17 signaling pathway is downregulated during ATLL. Our data suggest that boosting the RORC/IL-17 signaling pathway in ATLL and using anti-IL-17 agents in HAM/TSP and other HTLV-related inflammatory conditions might benefit patients and improve their outcomes.

Precise excision of HTLV-1 provirus with a designer-recombinase.

The human T cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that persists as a provirus in the genome of infected cells and can lead to adult T cell leukemia (ATL). Worldwide, more than 10 million people are infected and approximately 5% of these individuals will develop ATL, a highly aggressive cancer that is currently incurable. In the last years, genome editing tools have emerged as promising antiviral agents. In this proof-of-concept study, we use substrate-linked directed evolution (SLiDE) to engineer Cre-derived site-specific recombinases to excise the HTLV-1 proviral genome from infected cells. We identified a conserved loxP-like sequence (loxHTLV) present in the long terminal repeats of the majority of virus isolates. After 181 cycles of SLiDE, we isolated a designer-recombinase (designated RecHTLV), which efficiently recombines the loxHTLV sequence in bacteria and human cells with high specificity. Expression of RecHTLV in human Jurkat T cells resulted in antiviral activity when challenged with an HTLV-1 infection. Moreover, expression of RecHTLV in chronically infected SP cells led to the excision of HTLV-1 proviral DNA. Our data suggest that recombinase-mediated excision of the HTLV-1 provirus represents a promising approach to reduce proviral load in HTLV-1-infected individuals, potentially preventing the development of HTLV-1-associated diseases.

HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load.

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1ß or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

HTLV-1 oncovirus-host interactions: From entry to the manifestation of associated diseases.

Human T lymphotropic virus type-1 (HTLV-1) is a well-known human oncovirus, associated with two life-threatening diseases, adult T cell leukaemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The study of this oncogenic virus is significant from two different aspects. First, HTLV-1 can be considered as a neglected public health problem, which may spread slowly worldwide. Second, the incidence of HTLV-1 associated diseases due to oncogenic effects and deterioration of the immune system towards autoimmune diseases are not fully understood. Furthermore, knowledge about viral routes of transmission is important for considering potential interventions, treatments or vaccines in endemic regions. In this review, novel characteristics of HTLV-1, such as the unusual infectivity of virions through the virological synapse, are discussed in the context of the HTLV-1 associated diseases (ATL and HAM/TSP).

The IL-18, IL-12, and IFN-γ expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, HTLV-1 carriers, and healthy subjects.

Interleukin (IL)-12, IL-18, and interferon gamma (IFN-γ) can induce Th1-inflammatory responses in favor of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) manifestation. In this study, the gene expression and plasma levels of these cytokines were evaluated. The peripheral blood mononuclear cells (PBMCs) in 20 HAM/TSP patients, 21 asymptomatic carriers (ACs), and 21 healthy subjects (HSs) were assessed for the expression of IL-18, IL-12, and IFN-γ, using qRT-PCR. The plasma level of IL-18 and IFN-γ were measured by an ELISA method. The mean of HTLV-1 proviral load (PVL) in the HAM/TSPs was 1846.59 ± 273.25 and higher than ACs at 719.58 ± 150.72 (p = 0.001). The IL-12 was considerably expressed only in nine ACs, five HAM/TSPs, and all HSs. Furthermore, the gene expression and plasma levels of IL-18 were lower in the HTLV-1-positive group than the control group (p = 0.001 and 0.012, respectively); however, there was no significant difference between the ACs and HAM/TSPs. The IFN-γ level was higher in the HTLV-1-positive group (p < 0.001) than HSs. Although there were no correlation between plasma levels of IL-18 and IFN-γ with PVL in the ACs, a positive correlation was observed between plasma IL-18 levels and PVL (r = 0.654, p = 0.002). The highest levels of IFN-γ were observed in the HAM/TSPs which has a significant correlation with HTLV-1-HBZ (r = 0.387, p = 0.05) but not with Tax. However, no significant correlation was found between PVL and proinflammatory pattern. Apart from the IFN-γ as a lymphokine, as a host factor, and HTLV-1-HBZ, as a viral agent, the other proinflammatory monokines or HTLV-1 factors are among the less-effective agents in the maintenance of HAM/TSP.

Expression of TSLC1 in patients with HAM/TSP.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic myelopathy characterized by slowly progressive spastic paraparesis and urinary dysfunction. A few biomarkers in the cerebrospinal fluid are known to be related to disease activity, but no biomarker has been reported in peripheral blood. This study aims to explore the expression level of the adhesion molecule during the expression level of the adhesion molecule among HAM/TSP disease activity. In lymphocyte function-associated antigen 1 and DNAX accessory molecule 1, no variation in expression levels specific to HTLV-1 infection was observed in CD4-positive T cells; however, TSLC1 expression was higher in HAM patients than in asymptomatic carriers and non-infected persons. TSLC1 tended to be higher in patients whose symptoms were worsening. On the contrary, the expression level of TSLC1 in CD8-positive T cells was lower in HAM patients than in asymptomatic carriers, and this tendency was stronger in patients whose symptoms had deteriorated. No significant correlation was found between TSLC1 and either of the transcription factors Tax or HBZ in any T cell group. Therefore, TSLC1 expression in CD4-positive T cells might be a useful biomarker of HAM/TSP disease activity.

An insight to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high-throughput data integration and meta-analysis.

BACKGROUND: Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. RESULTS: High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein-protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). CONCLUSIONS: High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.

Comparative virology of HTLV-1 and HTLV-2.

Human T cell leukemia virus type 1 (HTLV-1) was the first discovered human retrovirus and the etiologic agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Shortly after the discovery of HTLV-1, human T-cell leukemia virus type 2 (HTLV-2) was isolated from a patient with hairy cell leukemia. Despite possession of similar structural features to HTLV-1, HTLV-2 has not been definitively associated with lymphoproliferative disease. Since their discovery, studies have been performed with the goal of highlighting the differences between HTLV-1 and HTLV-2. A better understanding of these differences will shed light on the specific pathogenic mechanisms of HTLV-1 and lead to novel therapeutic targets. This review will compare and contrast the two oldest human retroviruses with regards to epidemiology, genomic structure, gene products, and pathobiology.

p30 protein: a critical regulator of HTLV-1 viral latency and host immunity.

The extraordinarily high prevalence of HTLV-1 subtype C (HTLV-1C) in some isolated indigenous communities in Oceania and the severity of the health conditions associated with the virus impress the great need for basic and translational research to prevent and treat HTLV-1 infection. The genome of the virus's most common subtype, HTLV-1A, encodes structural, enzymatic, and regulatory proteins that contribute to viral persistence and pathogenesis. Among these is the p30 protein encoded by the doubly spliced Tax-orf II mRNA, a nuclear/nucleolar protein with both transcriptional and post-transcriptional activity. The p30 protein inhibits the productive replication cycle via nuclear retention of the mRNA that encodes for both the viral transcriptional trans-activator Tax, and the Rex proteins that regulate the transport of incompletely spliced viral mRNA to the cytoplasm. In myeloid cells, p30 inhibits the PU-1 transcription factor that regulates interferon expression and is a critical mediator of innate and adaptive immunity. Furthermore, p30 alters gene expression, cell cycle progression, and DNA damage responses in T-cells, raising the hypothesis that p30 may directly contribute to T cell transformation. By fine-tuning viral expression while also inhibiting host innate responses, p30 is likely essential for viral infection and persistence. This concept is supported by the finding that macaques, a natural host for the closely genetically related simian T-cell leukemia virus 1 (STLV-1), exposed to an HTLV-1 knockout for p30 expression by a single point mutation do not became infected unless reversion and selection of the wild type HTLV-1 genotype occurs. All together, these data suggest that inhibition of p30 may help to curb and eventually eradicate viral infection by exposing infected cells to an effective host immune response.

Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence.

The human T cell leukemia virus type 1 (HTVL-1), first reported in 1980 by Robert Gallo's group, is the etiologic agent of both cancer and inflammatory diseases. Despite approximately 40 years of investigation, the prognosis for afflicted patients remains poor with no effective treatments. The virus persists in the infected host by evading the host immune response and inducing proliferation of infected CD4+ T-cells. Here, we will review the role that viral orf-I protein products play in altering intracellular signaling, protein expression and cell-cell communication in order to escape immune recognition and promote T-cell proliferation. We will also review studies of orf-I mutations found in infected patients and their potential impact on viral load, transmission and persistence. Finally, we will compare the orf-I gene in HTLV-1 subtypes as well as related STLV-1.

Human T-Cell Lymphotropic Virus Type 1 and associated diseases in Latin America.

This narrative review, which is based on a systematic literature search following the PRISMA guidelines, provides a general overview of Human T-cell Lymphotropic Virus type 1 (HTLV-1) and associated diseases: Adult T-cell Leukaemia-Lymphoma (ATLL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in Latin America, focusing on epidemiology and prevention. Using the published information on HTLV-1, ATLL and HAM/TSP prevalence, we present comprehensive and accurate maps and tables, and developed an algorithm to assist in the prevention of HTLV-1 transmission through breastfeeding while considering socio-economic status. Latin America is an interesting scenario to study HTLV-1 because of the diverse origin of its population. Apart from the expected high prevalence in inhabitants of African ancestry, the presence of endemic foci affecting indigenous populations is particularly striking. ATLL prevention is the biggest challenge in this field. Most ATLL cases are transmitted through breastfeeding; thus, prevention methods to avoid ATLL in endemic countries have to be focused on this. In view of the high inequality in most Latin American countries, reduction in breastfeeding duration, freezing/thawing and pasteurisation of breastmilk can be suitable interventions in poor settings, considering that avoiding the risk of malnutrition and infant mortality must be the priority.

Cette revue narrative, qui repose sur une recherche bibliographique systématique conforme aux recommandations de PRISMA, fournit un aperçu général sur le virus lymphotropique des lymphocytes T humaines de type 1 (HTLV-1) et les maladies associées: Le lymphome leucémique des cellules T d'adulte (ATLL)) et la myélopathie/paraparésie spastique tropicale (HAM/TSP) associée à HTLV-1 en Amérique latine, en se focalisant sur l'épidémiologie et la prévention. En utilisant les informations publiées sur la prévalence de HTLV-1, ATLL et HAM/TSP, nous présentons des cartes et des tableaux complets et précis et avons développé un algorithme pour aider à la prévention de la transmission du HTLV-1 par l'allaitement tout en tenant compte du statut socioéconomique. L'Amérique latine est un scénario intéressant pour l'étude de HTLV-1 en raison de la diversité des origines de sa population. Outre la forte prévalence escomptée chez les habitants de descendance africaine, la présence de foyers endémiques affectant les populations autochtones est particulièrement frappante. La prévention de l'ATLL est le plus gros défi dans ce domaine. La plupart des cas d'ATLL sont transmis par l'allaitement. Ainsi, les méthodes de prévention pour éviter l'ATLL dans les pays d'endémie doivent être concentrées sur cela. Compte tenu de la forte inégalité qui règne dans la plupart des pays d'Amérique latine, la réduction de la durée de l'allaitement, la congélation/décongélation et la pasteurisation du lait maternel peuvent constituer des interventions appropriées dans les milieux pauvres, tout en considérant que la priorité est d'éviter les risques de malnutrition et de mortalité infantile.

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.

Interferon Lambda Family along with HTLV-1 Proviral Load, Tax, and HBZ Implicated in the Pathogenesis of Myelopathy/Tropical Spastic Paraparesis.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disease related to human T lymphotropic virus type 1 (HTLV-1) infection. Interferon type III (IFN-λ), which includes IL28, IL29, and IL28R, and affects the outcome of viral infections, might be complicated in the progression of HAM/TSP. Here, we investigated the host-virus interactions in the manifestation of HAM/TSP, using IL28B, IL29, IL28R, HTLV-1 Tax, HTLV-1 basic leucine zipper factor (HBZ), and proviral load (PVL). The study groups consisted of 20 patients with HAM/TSP, 20 asymptomatic HTLV-1 carriers (ACs), and 20 healthy controls (HCs). The means of PVL, Tax, and HBZ gene expressions in the HAM/TSP group (p = 0.004, 0.006, and < 0.0001, respectively) were significantly higher than in the AC group. The comparison of IL28B, IL29, and IL28R expression in the HAM/TSP, AC, and HC groups revealed no significant difference between the first 2, but lower concentrations in the HCs (IL28B: p = 0.03, 0.01; IL29: p = 0.07, 0.01; and IL28R: p < 0.0001, respectively). In the HAM/TSP group, correlations were seen between Tax and HBZ (R = 0.61, p = 0.004) and between Tax and IL29 (R = 0.45, p = 0.04). Negative correlations were observed between Tax and IL28B (R = -0.49, p = 0.02) and between HBZ and IL28R (R = -0.43, p = 0.06). In the ACs, an inverse correlation was found between Tax and IL28B (R = -0.42, p = 0.06). These findings suggest that IL29, IL28B, and IL28R interfere in the infection of HAM/TSP, mainly via Tax activation.

Infective dermatitis associated with human T-cell lymphotropic virus type-1, an underdiagnosed disease.

Infective dermatitis associated with human T-cell lymphotropic virus type-1 (HTLV-1) (IDH) is a severe form of chronically infected eczema occurring in early childhood, although very rarely cases have been reported in adults. Most of the cases are from Jamaica and Brazil and occur in individuals with low socioeconomic status. IDH is always associated with refractory Staphylococcus aureus or beta-hemolytic Streptococcus infection of the skin and nasal vestibules. Patients with IDH may develop other even more severe HTLV-1-associated diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) of early or late appearance and adult T-cell leukemia/lymphoma. In the context of the Brazilian experience, it has been observed that 54% of IDH patients exhibit the juvenile form of HAM/TSP while the estimated incidence of adult HAM/TSP is 3%. As there are no curative treatments for HTLV-1 infection (or vaccines) or most of its associated diseases, prevention of infection is fundamental, mainly by vertical transmission, as it is responsible for the development of IDH, infantojuvenile HAM/TSP, and ATL. Public measures to reduce this transmission must be implemented urgently. Furthermore, it is recommended, mainly in HTLV-1 endemic areas, to search for HTLV-1 infection in all patients with infected eczema, even in adults.

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells.

The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1ß were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.

Cannabinoid receptors as new targets for HTLV-1 associated myelopathy (HAM/TSP) treatment.

BACKGROUND/AIM: The roles of endocannabinoids are described in immune modulation and neuroprotection. HTLV-1-associated myelopathy (HAM/TSP) is an inflammatory neurodegenerative disease. Therefore, in this study, the interactions of HTLV-1 regulatory factors and host cannabinoid receptors (CBRs) were evaluated in HAM/TSP. METHODS: Nineteen HAM/TSPs, 22 asymptomatic carriers (ACs), and 18 healthy controls (HCs) were enrolled. RNA was extracted from PBMCs and then reverse-transcribed to cDNA. The gene expression of CB1R and CB2R, as well as HTLV-1 proviral load (PVL), Tax and HTLV-1 basic leucine zipper factor (HBZ) were assessed by RT-qPCR. RESULTS: The mean expression of CB1R in ACs (8.51 ± 2.76) was significantly higher than HAMTSPs (1.593 ± 0.74, p = 0.05) and also HCs (0.10 ± 0.039, p = 0.001). The CB2R gene expression level in ACs (2.62±0.44) was significantly higher than HAM/TSPs (0.59 ± 0.15, p = 0.001) and HCs (1.00 ± 0.2, p = 0.006). Meanwhile there was a strong correlation between CB1R and CB2R gene expression levels in the HCs and HAM/TSPs (p = 0.001). HTLV-1-Tax expression in HAM/TSPs (386 ± 104) was higher than ACs (75 ± 32) and statistically significant (p = 0.003). While HTLV-1-HBZ was only expressed in three AC subjects and five HAM/TSPs, thus it cannot be analyzed. CONCLUSION: The up-regulation of CB2R has immunomodulatory effects in inflammatory reactions. While CB1R as a neuroprotective agent may suppress inflammatory reactions in ACs, preventing HAM/TSP. It seems that, like multiple sclerosis (MS), cannabinoid medications are beneficial in HAM/TSP.

Th17/IL-17 Axis in HTLV-1-Associated Myelopathy Tropical Spastic Paraparesis and Multiple Sclerosis: Novel Insights into the Immunity During HAMTSP.

Human T lymphotropic virus-associated myelopathy/tropical spastic paraparesis (HTLV/TSP), also known as HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and multiple sclerosis (MS) are chronic debilitating diseases of the central nervous system; although the etiology of which is different, similarities have been observed between these two demyelinating diseases, especially in clinical manifestation and immunopathogenesis. Exorbitant response of the immune system to the virus and neurons in CNS is the causative agent of HAM/TSP and MS, respectively. Helper T lymphocyte-17 cells (Th17s), a component of the immune system, which have a proven role in immunity and autoimmunity, mediate protection against bacterial/fungal infections. The role of these cells has been reviewed in several CNS diseases. A pivotal role for Th17s is presented in demyelination, even more axial than Th1s, during MS. The effect of Th17s is not well determined in HTLV-1-associated infections; however, the evidence that we have supplied in this review illustrates the attendance, also the role of Th17 cells during HAM/TSP. Furthermore, for better conception concerning the trace of these cells in HAM/TSP, a comparative characterization with MS, the resembling disease, has been applied here.

The mirror like expression of genes involved in the FOXO signaling pathway could be effective in the pathogenesis of human lymphotropic virus type 1 (HTLV-1) through disruption of the downstream pathways.

OBJECTIVES: Human lymphotropic virus type 1 (HTLV-1) is the cause of two major diseases, ATLL and HAM/TSP in a percentage of carriers. Despite progress in understanding the pathogenesis of these two diseases, the exact pathogenesis mechanism is still not well understood. High-throughput technologies have revolutionized medical research. This study aims to investigate the mechanism of pathogenesis of these two diseases using the results of high-throughput analysis of microarray datasets. RESULTS: A total of 100 differentially expressed genes were found between ATLL and HAM/TSP. After constructing protein-protein network and further analyzing, proteins including ATM, CD8, CXCR4, PIK3R1 and CD2 were found as the hub ones between ATLL and HAM/TSP. Finding the modules of the subnetwork revealed the enrichment of two common pathways including FOXO signaling pathway and Cell cycle with two common genes including ATM and CDKN2D. Unlike ATLL, ATM gene had higher expressions in HAM/TSP patients. The expression of CDKN2D was increased in ATLL patients. The results of this study could be helpful for understanding the pathogenic mechanism of these two diseases in the same signaling pathways.

HTLV-1-associated demyelinating neuropathy: A case report and review of the literature.

A 78-year-old man developed paresthesias in the extremities. He was referred to our hospital because of positive anti-human T-cell leukemia virus type 1 (HTLV-1) antibodies in the serum and the presence of abnormal lymphocytes. He was diagnosed as chronic-type adult T-cell leukemia/lymphoma. Neurological examination revealed sensory impairment in the distal parts of the extremities with loss of deep tendon reflexes. Nerve conduction study showed motor and sensory demyelinating polyneuropathy, indicating a diagnosis of HTLV-1-associated demyelinating neuropathy. Corticosteroid therapy followed by intravenous immunoglobulin therapy improved his symptoms. Since demyelinating neuropathy associated with HTLV-1 infection is not well recognized, we here report its characteristics and clinical course through our case report and literature review.