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Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally. It is endemic to certain First Nations populations of Northern and Central Australia, Japan, South and Central America, Africa, and the Caribbean region. HTLV-1 preferentially infects CD4+ T cells and remains in a state of reduced transcription, often being asymptomatic in the beginning of infection, with symptoms developing later in life. HTLV-1 infection is implicated in the development of adult T cell leukaemia/lymphoma (ATL) and HTLV-1-associated myelopathies (HAM), amongst other immune-related disorders. With no preventive or curative interventions, infected individuals have limited treatment options, most of which manage symptoms. The clinical burden and lack of treatment options directs the need for alternative treatment strategies for HTLV-1 infection. Recent advances have been made in the development of RNA-based antiviral therapeutics for Human Immunodeficiency Virus Type-1 (HIV-1), an analogous retrovirus that shares modes of transmission with HTLV-1. This review highlights past and ongoing efforts in the development of HTLV-1 therapeutics and vaccines, with a focus on the potential for gene therapy as a new treatment modality in light of its successes in HIV-1, as well as animal models that may help the advancement of novel antiviral and anticancer interventions. [ABSTRACT FROM AUTHOR]

Introduction: Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic to Brazil, and there is still no specific treatment for these patients. The literature shows that few studies have described the cognitive impairment associated with an HTLV-1 infection, with none of them examining the population of Salvador, where there are approximately forty thousand people infected with the virus. Objectives: To determine the prevalence of cognitive impairment among individuals with HTLV-1. In addition, investigate whether sociodemographic aspects, time since the diagnosis of infection, and the diagnosis of HTLV-Associated Myelopatia/Tropical Spastic Paraparesis (HAM/TSP) or depression are associated with cognitive impairment in this population. Methods: This was an observational, cross-sectional study that consisted of consecutively approaching 100 HTLV-1 patients during outpatient care at a referral center followed by the administration of three questionnaires— the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and Beck's Depression Inventory. Results: The prevalence of cognitive impairment found was 71% using the MMSE and 82% using the MoCA. There was a statistically significant association between the cognitive dysfunction and the variables of age and education according to the MoCA analysis but not the MMSE data. Diagnosis of HAM/TSP was correlated with cognitive impairment using the MMSE but not the MoCA. The prevalence of depression was 20%, and there was no association between cognitive impairment and depressive symptoms in these patients. Conclusions: The findings of this study demonstrate a correlation between cognitive dysfunction and HTVL-1 infection, with a more evident involvement of executive functions and memory. Larger studies are needed to clarify the association between cognitive dysfunction, age, education, and the diagnosis of HAM/TSP. [ABSTRACT FROM AUTHOR]

This is the first systematic review and meta-analysis to estimate the prevalence of human T-lymphotropic virus 1 and 2 (HTLV-1 and 2) infections among immigrants and refugees worldwide. PubMed/MEDLINE, Scopus, EMBASE, Web of Science, and Virtual Health Library (VHL) databases were searched for studies published from their inception to 6 January 2023. A meta-analysis using a generalized linear mixed model with a random effect was performed for HTLV-1 and HTLV-2. Subgroup analyses were performed based on the decade of study, sample size, confirmatory methods, region of study, risk group, and region of origin. Of the 381 studies initially identified, 21 were included. The pooled prevalence of HTLV-1 and HTLV-2 was 1.28% (95% CI: 0.58, 2.81) and 0.11% (95% CI: 0.04, 0.33), respectively. HTLV-1 prevalence differed significantly by region of origin, with the highest prevalence among those from the Western Pacific Region (7.27%; 95% CI: 2.94, 16.83). The subgroup analysis also showed significant differences between the estimates of HTLV-1 considering the decade of study, sample size, and region of study. For HTLV-2, significant differences were shown in relation to sample size, confirmatory methods, and risk group. The higher HTLV-1 prevalence found deserves public health attention in immigrant and refugee-receiving non-endemic countries. [ABSTRACT FROM AUTHOR]

Adult T-cell lymphoma/leukaemia (ATLL) is an aggressive T-cell lymphoma caused by the retrovirus HTLV-1. Its clinical presentation and course can be variable, and it may mimic other T-cell lymphomas or non-neoplastic entities. ATLL is commonly complicated by superadded Strongyloides infestation. In this setting, this can rapidly accelerate a patients demise, highlighting the need for awareness and vigilance of this dual diagnosis. [ABSTRACT FROM AUTHOR]

Human T‐cell Lymphotropic Virus Type 1 (HTLV‐1) is traditionally linked to severe conditions such as adult T‐cell leukemia/lymphoma, HTLV‐1‐associated myelopathy, and HTLV‐1 uveitis, with vertical transmission, particularly mother to child thorough breastfeeding, considered the primary route. Despite efforts to reduce vertical transmission through antenatal screening in Japan, horizontal transmission has contributed to the rising prevalence of HTLV‐1 in metropolitan areas. This case reports the youngest documented instance of HTLV‐1 uveitis resulting from horizontal transmission through sexual contact in an 18‐year‐old woman. The patient presented with blurred vision in her right eye, and a comprehensive ophthalmologic examination identified vitreous opacity and retinal vasculitis. Serological tests confirmed HTLV‐1 infection, with a proviral load of 2.66 copies per 100 peripheral blood mononuclear cells, measured by real‐time PCR. A differential diagnosis confirmed HTLV‐1 uveitis. Further family and partner investigations confirmed horizontal transmission, most likely through sexual contact. Over 6 years of follow‐up, the patient experienced multiple recurrences of HTLV‐1 uveitis and developed HTLV‐1‐associated keratopathy. This case highlights the potential for rapid disease progression with relatively low proviral loads and short latency, emphasizing the need for updated public health strategies for sexually active young populations. [ABSTRACT FROM AUTHOR]

Human T cell leukemia virus type 1 (HTLV-1) is the first human oncogenic retrovirus to be discovered and causes two major diseases: a progressive neuro-inflammatory disease, termed HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and an aggressive malignancy of T lymphocytes known as adult T cell leukemia (ATL). Innate and acquired immune responses play pivotal roles in controlling the status of HTLV-1-infected cells and such, the outcome of HTLV-1 infection. Natural killer cells (NKCs) are the effector cells of the innate immune system and are involved in controlling viral infections and several types of cancers. The ability of NKCs to trigger cytotoxicity to provide surveillance against viruses and cancer depends on the balance between the inhibitory and activating signals. In this review, we will discuss NKC function and the alterations in the frequency of these cells in HTLV-1 infection. [ABSTRACT FROM AUTHOR]

Background: Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) after a long latent infection. HTLV-1 induces the indolent or aggressive type of leukemia in 5% of HTLV-1 carriers. ATL, especially the aggressive type, is resistant to multi-agent chemotherapy. The indolent type often progresses to the aggressive type. Even in the most indolent-type cases, that is, smoldering ATL, the average survival time is 55.0 months. Case Presentation: Five patients with ATL were followed up for their clinical course after amplified natural killer cell (ANK) therapy. Four patients who received ANK therapy as first-line therapy achieved complete remission and showed long-term survival without aggressive conversion or relapse for more than 5 years. One patient was treated with multiagent chemotherapy due to acute exacerbation but relapsed 2 months later. She was subsequently treated with radiation and ANK therapy and survived for more than 6 years. Furthermore, ANK therapy enhanced the immune function of ATL patients to a level higher than that of normal individuals. Conclusions: ANK therapy has great potential as first-line treatment for ATL. [ABSTRACT FROM AUTHOR]

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive demyelinating disease of the spinal cord due to chronic inflammation. Hallmarks of disease pathology include dysfunctional anti-viral responses and the infiltration of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ T cells in the central nervous system. HAM/TSP individuals exhibit CD4+ and CD8+ T cells with elevated co-expression of multiple inhibitory immune checkpoint proteins (ICPs), but ICP blockade strategies can only partially restore CD8+ T-cell effector function. Exosomes, small extracellular vesicles, can enhance the spread of viral infections and blunt anti-viral responses. Here, we evaluated the impact of exosomes isolated from HTLV-1-infected cells and HAM/TSP patient sera on dendritic cell (DC) and T-cell phenotypes and function. We observed that exosomes derived from HTLV-infected cell lines (OSP2) elicit proinflammatory cytokine responses in DCs, promote helper CD4+ T-cell polarization, and suppress CD8+ T-cell effector function. Furthermore, exosomes from individuals with HAM/TSP stimulate CD4+ T-cell polarization, marked by increased Th1 and regulatory T-cell differentiation. We conclude that exosomes in the setting of HAM/TSP are detrimental to DC and T-cell function and may contribute to the progression of pathology with HTLV-1 infection. [ABSTRACT FROM AUTHOR]

The reasons that lead some individuals living with the Human T Lymphotropic Virus 1 (HTLV‐1) to develop HAM/TSP are still unclear. To better understand the viral genetic factors that may be associated with the development of HAM/TSP, this study aims to evaluate the impact of HTLV‐1 genome mutations on the development of this disease through a systematic review. This review followed the PRISMA guidelines and was registered in the PROSPERO database. The search for articles was performed in PMC, PubMed, Lilacs, SciELO, and Embase databases using the following search descriptors: HTLV‐1, HAM/TSP, mutation, polymorphism, genetic variation, and sequenc*. From the 1,929 articles found in the search, 20 were selected according to the pre‐defined inclusion and exclusion criteria. A total of 619 HAM/TSP cases were compared with 555 AC controls. The mutations possibly related to the disease progression were detected in hbz (R119Q), tax (A7959V), ORF‐I (R88K, P86S, S69G, P45L, L40F, C39R, CR9Y), and gp46 (V247I, N93D, S72G) genetic regions. The data collected and analyzed here indicate that mutations in the HTLV‐1 genome could play an important role in the chronic inflammatory state and may be related to the development of HAM/TSP. [ABSTRACT FROM AUTHOR]

HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a progressive non-remitting and incapacitating disease more frequently seen in women and with a patchy worldwide distribution. HAM/TSP develops in a small percentage of HTLV-1-infected individuals during their lifetime and etiologic factors for disease progression are still unclear. This study aims to describe the first case series of the progression of HAM/TSP in relation to pregnancy. Between January and March of 2012, we reviewed medical charts of women with HAM/TSP currently enrolled in the HTLV-1 cohort at the institute of tropical medicine of Cayetano Heredia University. Inclusion criteria included having a diagnosis of HAM/TSP according to the WHO guidelines and self-reported initial symptoms of HAM/TSP during pregnancy or within six months of delivery. Fifteen women reported having had symptoms compatible with HAM/TSP within four months of delivery. Among them, ten women had no symptoms before pregnancy and reported gait impairment after delivery. Five women with mild gait impairment before pregnancy noticed a worsening of their symptoms after delivery. Symptoms worsened after successive pregnancies. Recent studies have shown that HTLV-1 infection induces a strong T cell-mediated response and that the quality of this response plays a role in HAM/TSP pathogenesis. The relative immunosuppression during pregnancy, including blunting of the T-cell response, might allowed in certain women enhanced replication of HTLV-1 and disease progression in the postpartum. This is the first study looking specifically at HAM/TSP and pregnancy and the number of cases is remarkable. Further prospective studies of HTLV-1-infected women assessing immune markers during pregnancy are warranted. Breastfeeding was the main route of transmission. Strategies to prevent vertical transmission need to be evaluated in HTLV-1 endemic countries of Latin America. [ABSTRACT FROM AUTHOR]

Introduction Human T‐cell lymphotropic virus type 1 infection can cause HTLV‐1‐associated myelopathy/tropical spastic paraparesis, characterized by spastic paralysis of both lower limbs. More than 90% of HAM/TSP patients show lower urinary tract symptoms and dysfunction. Case presentation A 27‐year‐old woman diagnosed with HAM/TSP presented with overactive bladder. A urodynamic study revealed detrusor overactivity. OAB remained despite improvements in spastic paralysis of the lower limbs after starting prednisolone. The addition of solifenacin likewise failed to improve OAB or DO in this patient. Switching from solifenacin to vibegron improved OAB symptoms. Conclusion In patients for whom OAB and DO do not improve with steroid treatment and solifenacin, treatment with vibegron may improve OAB symptoms.

Abstract Human T-lymphotropic virus type 1 (HTLV-1) is a RNA virus belonging to Retroviridae family and is associated with the development of various diseases, including adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Aside from HAM/TSP, HTLV-1 has been implicated in the development of several disorders that mimic auto-inflammation. T-cell migration is important topic in the context of HTLV-1 associated diseases progression. The primary objective of this case–control study was to assess the relationship between increased mRNA expression in virus migration following HTLV-1 infection. PBMCs from 20 asymptomatic patients and 20 healthy subjects were analyzed using real-time PCR to measure mRNA expression of LFA1, MLCK, RAC1, RAPL, ROCK1, VAV1 and CXCR4. Also, mRNA expression of Tax and HBZ were evaluated. Mean expression of Tax and HBZ in ACs (asymptomatic carriers) was 0.7218 and 0.6517 respectively. The results revealed a noteworthy upregulation of these genes involved in T-cell migration among ACs patients in comparison to healthy individuals. Considering the pivotal role of gene expression alterations associated with the progression into two major diseases (ATLL or HAM/TSP), analyzing the expression of these genes in the ACs group can offer probable potential diagnostic markers and aid in monitoring the condition of ACs.

Abstract Background Simian T-cell leukemia virus type 1 (STLV-1) is a retrovirus closely related to human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia (ATL). It has been shown that Japanese macaques (Macaca fuscata, JMs) are one of the main hosts of STLV-1 and that a high percentage of JMs (up to 60%) are infected with STLV-1; however, the molecular epidemiology of STLV-1 in JMs has not been examined. Methods In this study, we analyzed full-length STLV-1 genome sequences obtained from 5 independent troops including a total of 68 JMs. Results The overall nucleotide heterogeneity was 4.7%, and the heterogeneity among the troops was 2.1%, irrespective of the formation of distinct subclusters in each troop. Moreover, the heterogeneity within each troop was extremely low (>99% genome homology) compared with cases of STLV-1 in African non-human primates as well as humans. It was previously reported that frequent G-to-A single-nucleotide variants (SNVs) occur in HTLV-1 proviral genomes in both ATL patients and HTLV-1 carriers, and that a G-to-A hypermutation is associated with the cellular antiviral restriction factor, Apobec3G. Surprisingly, these SNVs were scarcely observed in the STLV-1 genomes in JMs. Conclusions Taken together, these results indicate that STLV-1 genomes in JMs are highly homologous, at least in part due to the lack of Apobec3G-dependent G-to-A hypermutation.

Abstract Background Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-β. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. Methods Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-β-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. Results Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. Conclusions A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-β may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.

Human T-lymphotropic virus type 1 (HTLV-1) is a RNA virus belonging to Retroviridae family and is associated with the development of various diseases, including adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Aside from HAM/TSP, HTLV-1 has been implicated in the development of several disorders that mimic auto-inflammation. T-cell migration is important topic in the context of HTLV-1 associated diseases progression. The primary objective of this case–control study was to assess the relationship between increased mRNA expression in virus migration following HTLV-1 infection. PBMCs from 20 asymptomatic patients and 20 healthy subjects were analyzed using real-time PCR to measure mRNA expression of LFA1, MLCK, RAC1, RAPL, ROCK1, VAV1 and CXCR4. Also, mRNA expression of Tax and HBZ were evaluated. Mean expression of Tax and HBZ in ACs (asymptomatic carriers) was 0.7218 and 0.6517 respectively. The results revealed a noteworthy upregulation of these genes involved in T-cell migration among ACs patients in comparison to healthy individuals. Considering the pivotal role of gene expression alterations associated with the progression into two major diseases (ATLL or HAM/TSP), analyzing the expression of these genes in the ACs group can offer probable potential diagnostic markers and aid in monitoring the condition of ACs. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic virus type 1 (HTLV-1) is classically associated with the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although the mechanisms of this neurological disorder remain unclear. In addition, some patients who develop "minor" neurological signs that do not meet diagnostic criteria for HAM/TSP are classified as asymptomatic carriers. This study aims to demonstrate the neurological symptoms of Brazilian patients living with HTLV-1 classified as not-HAM.TSP. This observational study evaluated patients treated in an HTLV reference center in Bahia, Brazil, between February 2022 and July 2023. The data were obtained through the analysis of medical records and neurological consultation. Those individuals classified as HAM/ TSP were excluded from this study. 74 patients were submitted to a careful neurological evaluation: 23 HAM/TSP, 22 were classified with intermediate syndrome (IS), and 29 were oligosymptomatic. Self-reported symptoms were significantly more common in the IS group, including urinary symptoms such as nocturia, urgency, incontinence, dysuria, weakness, paresthesia, lumbar pain, xerostomia, and xerophthalmia. Physical examination findings consistent with reduced vibratory and tactile sensitivity were more common in the IS group (p = 0.017 and p = 0.013). Alterations in the V and VIII cranial nerves were present in both groups. HTLV-1 can lead to the development of important neurological signs and symptoms in apparently asymptomatic individuals. This data highlights the need for more research into the neurological aspects of HTLV-1 infection and emphasizes the importance of early diagnosis, treatment, and support for individuals living with this virus. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The trans-activator protein Tax of HTLV-1 plays crucial roles in leukemogenesis by promoting proliferation of virus-infected cells through activation of growth-promoting genes. However, critical target genes are yet to be elucidated. We show here that Tax activates the gene coding for cyclin-dependent kinase 7 (CDK7), the essential component of both CDK-activating kinase (CAK) and general transcription factor TFIIH. CAK and TFIIH play essential roles in cell cycle progression and transcription by activating CDKs and facilitating transcriptional initiation, respectively. Tax induced CDK7 gene expression not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs) along with increased protein expression. Tax stimulated phosphorylation of CDK2 and RNA polymerase II at sites reported to be mediated by CDK7. Tax activated the CDK7 promoter through the NF-κB pathway, which mainly mediates cell growth promotion by Tax. Knockdown of CDK7 expression reduced Tax-mediated induction of target gene expression and cell cycle progression. These results suggest that the CDK7 gene is a crucial target of Tax-mediated trans-activation to promote cell proliferation by activating CDKs and transcription. [ABSTRACT FROM AUTHOR]

Background: Simian T-cell leukemia virus type 1 (STLV-1) is a retrovirus closely related to human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia (ATL). It has been shown that Japanese macaques (Macaca fuscata, JMs) are one of the main hosts of STLV-1 and that a high percentage of JMs (up to 60%) are infected with STLV-1; however, the molecular epidemiology of STLV-1 in JMs has not been examined. Methods: In this study, we analyzed full-length STLV-1 genome sequences obtained from 5 independent troops including a total of 68 JMs. Results: The overall nucleotide heterogeneity was 4.7%, and the heterogeneity among the troops was 2.1%, irrespective of the formation of distinct subclusters in each troop. Moreover, the heterogeneity within each troop was extremely low (>99% genome homology) compared with cases of STLV-1 in African non-human primates as well as humans. It was previously reported that frequent G-to-A single-nucleotide variants (SNVs) occur in HTLV-1 proviral genomes in both ATL patients and HTLV-1 carriers, and that a G-to-A hypermutation is associated with the cellular antiviral restriction factor, Apobec3G. Surprisingly, these SNVs were scarcely observed in the STLV-1 genomes in JMs. Conclusions: Taken together, these results indicate that STLV-1 genomes in JMs are highly homologous, at least in part due to the lack of Apobec3G-dependent G-to-A hypermutation. [ABSTRACT FROM AUTHOR]

HIV-1, Hepatitis B and HTLV-1 have similar risk factors and shared routes of transmission and MSM are disproportionately affected by HIV. The aim of the study was to determine the prevalence of HTLV-1 and HBsAg positivity at initial enrolment among MSM attending a large HIV Clinic in Trinidad. Chart reviews were conducted between 2 and 15 January 2024, among self-identified MSM and a comparative group of randomly selected self-identified heterosexual males where sociodemographic, clinical and laboratory data were collected and analysed using SPSS Version 25. During the period April 2002–31 October 2023, in total there were 10,424 patients registered at the clinic, of whom 1255 (12.0%) were self-identified MSM, with an age range of 19–85 years and a median age of 40 years. There were 1822 randomly selected heterosexual males, with an age range of 18–94 years old and a median age of 52 years. Among the MSM, there were 21 (1.67%) patients who were HIV-1/HTLV-1-coinfected, 64 (5.10%) who were HIV-1/HBsAg-coinfected and two (0.16%) who were coinfected with all three viruses (HIV-1/HTLV-1/HBsAg) as compared to 47 ((2.58%) HIV-1/HTLV-1-coinfected (p = 0.12), 69 (3.79%) HIV-1/HBsAg-coinfected (p = 0.10) and three (0.16%) patients coinfected with all three viruses among the heterosexual males. There were no patients with HTLV-1-related diseases among the HIV-1/HTLV-1-coinfected patients and there were no deaths from chronic liver disease in patients coinfected with HIV-1/HBsAg. Despite the availability of an efficacious vaccine, there is a prevalence of hepatitis B of 5.1% among MSM attending the HIV Clinic in Trinidad; therefore, programmes to increase health literacy, screening and immunization are urgently needed. [ABSTRACT FROM AUTHOR]

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997--2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Ra, IL-27) or HAM (IL-29/IFN-l1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients. [ABSTRACT FROM AUTHOR]

Human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects lymphocytes and causes severe diseases. HTLV-1 proviral load (PVL), i.e., the number of host cells that carry HTLV-1 proviral DNA integrated into their genome, can be measured in peripheral blood mononuclear cells (PBMCs) using quantitative polymerase chain reaction. In this narrative review, we discuss the usefulness of HTLV-1 PVL quantification and share our experience acquired during more than 30 years of follow-up of people living with HTLV-1 in the UK. Patients with HTLV-1-associated myelopathy have higher PVL than those with asymptomatic infection. This is consistent across studies in different countries. High PVL predates symptom onset for both inflammatory and proliferative diseases. High PVL is essential but not sufficient for the development of HTLV-1-associated diseases. Therefore, PVL quantification can be used to support the care of people living with HTLV-1 by identifying those most at risk of HTLV-1-associated diseases. [ABSTRACT FROM AUTHOR]

Background: Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-β. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. Methods: Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-β-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. Results: Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. Conclusions: A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-β may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients. [ABSTRACT FROM AUTHOR]

Background and Objectives Human lymphotropic virus type I mainly infects lymphocytes. For the detection of this virus, mainly nucleated cells are evaluated. Due to the short longevity of cells, sample collection is a challenge. The purpose of the study was to investigate the presence of HTLV-1 virus in genomic DNA released from cells in plasma and to determine its viral load in Western blotpositive blood donors Materials and Methods In this descriptive study, 30 HTLV-1 positive Western blot donors were evaluated. Using an extraction kit, genomic DNA was extracted from plasma and isolated PBMC using Ficol. A nested PCR test was used to confirm the presence of HTLV-1 virus. A real-time PCR quantitative test by Sybergreen method was used to determine the amount of virus load Results The average age of subjects was 42.9 ± 13.5 years; 93.3% of them were male and 6.6% female. LTR gene region was detected by nested PCR method in 80% of plasma and 100% of PBMC samples. The median viral loads in plasma and PBMC were 1.90 Copies/µL and 20 copies/106 PBMC, respectively. Conclusions To detect the HTLV-1 virus by molecular method, the HTLV-1 provirus DNA released from cells, in the plasma can be used when peripheral blood mononuclear cells are unavailable. It has also been observed that the virus load in the plasma of asymptomatic carriers is approximately 10 times lower than in PBMC. [ABSTRACT FROM AUTHOR]

With an estimated 10 million people infected, the deltaretrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the second most prevalent pathogenic retrovirus in humans after HIV-1. Like HIV-1, HTLV-1 overwhelmingly persists in a host via a reservoir of latently infected CD4+ T cells. Although most patients are asymptomatic, HTLV-1-associated pathologies are often debilitating and include adult T-cell leukaemia/lymphoma (ATLL), which presents in mature adulthood and is associated with poor prognosis with short overall survival despite treatment. Curiously, the strongest indicator for the development of ATLL is the acquisition of HTLV-1 through breastfeeding. There are no therapeutic or preventative regimens for HTLV-1. However, antiretrovirals (ARVs), which target the essential retrovirus enzymes, have been developed for and transformed HIV therapy. As the architectures of retroviral enzyme active sites are highly conserved, some HIV-specific compounds are active against HTLV-1. Here, we expand on our work, which showed that integrase strand transfer inhibitors (INSTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs) block HTLV-1 transmission in cell culture. Specifically, we find that dolutegravir, the INSTI currently recommended as the basis of all new combination antiretroviral therapy prescriptions, and the latest prodrug formula of the NRTI tenofovir, tenofovir alafenamide, also potently inhibit HTLV-1 infection. Our results, if replicated in a clinical setting, could see transmission rates of HTLV-1 and future caseloads of HTLV-1-associated pathologies like ATLL dramatically cut via the simple repurposing of already widely available HIV pills in HTLV-1 endemic areas. Considering our findings with the old medical saying "it is better to prevent than cure", we highly recommend the inclusion of INSTIs and tenofovir prodrugs in upcoming HTLV-1 clinical trials as potential prophylactics. [ABSTRACT FROM AUTHOR]

Simple Summary: French Guiana has a high prevalence of HIV and HTLV-1; its population is ethnically mixed, with widespread poverty, and up to 20% of the population lives in geographic isolation. These singular conditions suggest that the epidemiology of hematological malignancies may also be unusual. We, therefore, studied the incidence and mortality of different hematological malignancies and described factors associated with case fatality. The standardized incidence rate for hematological malignancies was 32.9 per 100,000 male years and 24.5 per 100,000 female years. Multiple myeloma and adult t-cell lymphoma/leukemia due to HTLV-1 infection were the two most common hematologic malignancies and causes of death. People born in a foreign country had a poorer case-fatality rate, presumably reflecting difficulties in accessing care. The epidemiology of hematological malignancies in French Guiana has features that distinguish it from mainland France or from Latin America. French Guiana is a French Overseas territory with singular features: it has a high prevalence of HIV and HTLV-1, its population is ethnically mixed, with widespread poverty, and up to 20% of the population lives in geographic isolation. In this context, we used registry data to estimate incidence and mortality due to hematological malignancies and to compare them with France and tropical Latin America. ICD codes C90 and C88 were compiled between 2005 and 2014. The direct standardization of age structure was performed using the world population. Survival analysis was performed, and Kaplan–Meier curves were drawn. The overall standardized incidence rate was 32.9 per 100,000 male years and 24.5 per 100,000 female years. Between 2005 and 2009, the standardized incidence rate was 29.6 per 100,000 among men and 23.6 per 100,000 among women, and between 2010 and 2014, it was 35.6 per 100,000 among men and 25.2 per 100,000 among women. Multiple myeloma/plasmocytoma and mature t/NK cell lymphomas, notably adult t-cell lymphoma/leukemia due to HTLV-1 infection, were the two most common hematologic malignancies and causes of death. Non-Hodgkin's lymphoma incidence estimates were greater than global estimates. After adjusting for age, sex, and type of malignancy, people born in a foreign country independently had a poorer case-fatality rate, presumably reflecting difficulties in accessing care. The epidemiology of hematological malignancies in French Guiana has features that distinguish it from mainland France or from Latin America. The incidence of multiple myeloma and adult t-cell lymphoma/leukemia was significantly greater in French Guiana than in France or other Latin American countries. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma. The oncogene product Tax of HTLV-I is thought to play crucial roles in leukemogenesis by promoting proliferation of the virus-infected cells through activation of growth-promoting genes. These genes code for growth factors and their receptors, cytokines, cell adhesion molecules, growth signal transducers, transcription factors and cell cycle regulators. We show here that Tax activates the gene coding for coactivator-associated arginine methyltransferase 1 (CARM1), which epigenetically enhances gene expression through methylation of histones. Tax activated the Carm1 gene and increased protein expression, not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs). Tax increased R17-methylated histone H3 on the target gene IL-2Rα, concomitant with increased expression of CARM1. Short hairpin RNA (shRNA)-mediated knockdown of CARM1 decreased Tax-mediated induction of IL-2Rα and Cyclin D2 gene expression, reduced E2F activation and inhibited cell cycle progression. Tax acted via response elements in intron 1 of the Carm1 gene, through the NF-κB pathway. These results suggest that Tax-mediated activation of the Carm1 gene contributes to leukemogenic target-gene expression and cell cycle progression, identifying the first epigenetic target gene for Tax-mediated trans-activation in cell growth promotion. [ABSTRACT FROM AUTHOR]

Purpose: to investigate secondary glaucoma resulting from uveitis in a patient infected with Human T-cell Leukemia Virus Type 1 (HTLV-1) pathologically and discuss the management of glaucoma with recurrent uveitis. Clinical course: An octogenarian woman diagnosed as a carrier of HTLV-1 experienced recurrent uveitis and a sudden rise in intraocular pressure (IOP) in both eyes. Due to the uncontrolled IOP and severely damaged visual field in her left eye, a combined procedure of trabeculectomy and DGIS (glaucoma drainage implant surgery, Baerveldt 350) was performed. The presence of HTLV-1 provirus was detected in the aqueous humor. Her trabeculectomy sample was processed for light microscopic observation. Following an irregular follow-up, she presented with a sudden decrease in vision and pain in her fellow eye, four years after the glaucoma surgeries. Her right eye exhibited a significant accumulation of mutton-fat-like keratic precipitates. Results: Clinical manifestations revealed the presence of granulomatous uveitis. The combined glaucoma surgery, along with continuous topical corticosteroid medication post-surgery in her left eye, effectively suppressed the high IOP spikes and the recurrence of uveitis for 4 years. The pathological examination of the outflow pathways showed a range of damages in Schlemm's canal (SC), including SC endothelial loss, narrowing, and occlusion, as well as loss of trabecular meshwork (TM) cells and fused TM beams. Conclusion: Combined GDIS and trabeculectomy represents a promising approach for managing such refractory cases of secondary glaucoma. Continuous topical corticosteroid medication is strongly recommended to prevent irreversible changes in SC and TM associated with granulomatous uveitis. [ABSTRACT FROM AUTHOR]

A silent spread of human T cell lymphotropic virus type 1 (HTLV-1) has been occurring for thousands of years, with a high prevalence in some regions due to the sexual and vertical transmission and formation of family clusters. The time from HTLV-1 infection until the onset of virus-associated diseases is extremely long, approximately one to three decades. In this study, we evaluated intrafamilial HTLV-1 transmission and associated diseases in 1,204 individuals enrolled and followed up by the GIPH cohort between 1997 and 2017. The family groups (n = 43) were composed of 279 individuals who were tested for HTLV-1/human T cell lymphotropic virus type 2 (HTLV-2) and were classified as two groups according to the index case: blood donor (blood donors referred to the GIPH cohort) and nondonor (individuals referred to the GIPH cohort by other health services). The observed rates of HTLV-1 transmission and associated diseases among the relatives were high. Of 236 family members and sexual partners tested for HTLV, 104 (44.1%) were confirmed as having HTLV infection, with 36.7% of relatives whose index case was blood donors and 56.9% of relatives with nondonor index cases. At least one case of HTLV-1-associated myelopathy was observed in 42.9% of the families with intrafamilial transmission of HTLV-1. Brazil is an endemic area for HTLV-1/2 and has implemented mandatory universal screening of blood donors for HTLV-1/2 since 1993. However, the lack of public health services offer diagnosis for HTLV to the general population and pregnant women in the country makes it difficult to identify infected people, and contributes to the silent spread of the virus. [ABSTRACT FROM AUTHOR]

Background and Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1). ATLL is a rare disease, found more frequently in HTLV-1-endemic areas, Romania being one of them. Despite treatment advances, the prognosis remains dismal. We aimed to describe the clinical, biological, and survival outcome features of Romanian patients with aggressive-type ATLL. Materials and Methods: We report the data of a prospective, observational, and unicentric study of all 20 patients diagnosed with lymphoma and acute types of ATLL at our center over the past 12 years. Data were collected from the patients' medical records. Results: Lymphoma-type ATLL (60%) was more common than acute-type ATLL (40%). Median age at diagnosis was 40.5 years, and most patients were female. Laboratory data revealed significant differences between acute and lymphoma-type ATLL, namely, higher leukocyte (p = 0.02) and lymphocyte counts (p = 0.02) and higher levels of corrected calcium (p = 0.001) in acute-type ATLL. All patients received chemotherapy, and only two underwent allogeneic stem cell transplantation. Only six patients obtained a complete or partial response to chemotherapy, mostly the lymphoma-type ones. The median survival for all patients was 6.37 months, with higher survival in the lymphoma-type ATLL (8.16 months) than in the acute-type (3.60 months). Normal calcium levels (p = 0.011), uric acid (p = 0.005), BUN score (p = 0.000), JCOG-PI moderate risk (p = 0.038), and obtaining complete or partial response (p = 0.037) were associated with higher survival. Conclusion: Aggressive-type ATLL among Romanian patients presents distinct characteristics, including younger age at diagnosis, female predominance, and higher incidence of lymphoma-type ATLL compared to currently reported data. Survival remains very low, with all subtypes experiencing a median survival of less than one year. [ABSTRACT FROM AUTHOR]

IntroductionThere is a lack of data on human T-lymphotropic virus 1 (HTLV-1) infection among transgender women (TGW). Therefore, this study estimated the prevalence of HTLV-1 infection in a group of TGW in Brazil.MethodsA cross-sectional study was conducted with 235 TGW in Goiânia City, Central Brazil. Respondent-driven sampling was used for recruitment. All participants were interviewed, and serum samples were tested for anti-HTLV-1/2 using an enzyme-linked immunosorbent assay (ELISA; Murex HTLV-I + II, DiaSorin, Dartford, United Kingdom). Seropositive samples were submitted for confirmation by Western blot (WB; MP Diagnostics HTLV BLOT 2.4 test, MP Biomedicals, Germany).ResultsThe majority of participants were young (≤ 25 years old), self-declared mixed or brown ethnicity, single, had attended high school, and had a monthly income above US$ 255 (R$ 1,000,00; nearly the minimum wage in Brazil at the time). Most reported earlier age at first sex and various risk behaviors for sexually transmitted infections (STIs). Three TGW were anti-HTLV-1/2 positive by ELISA and were subsequently positive for HTLV-1 by WB, giving a crude HTLV-1 seroprevalence of 1.3%; 1.0% (95% CI: 0.0–1.9) after being weighted by RDS Analysis Tool (RDSAT). The HTLV-1 seropositive TGW reported high-risk sexual behaviors. In addition, one of them also engaged in injecting drug use.ConclusionThese data indicate the circulation of HTLV-1 in TGW in Goiânia City, Central Brazil. Given the alarming estimates of high-risk sexual behaviors, there is an urgent need to intensify health programs targeting this population to control and prevent HTLV-1 and other STIs effectively.

BackgroundT-SPOT.TB®, one of the screening tests for latent tuberculosis infection (LTBI), yields invalid results in human T-cell leukemia virus type 1 (HTLV-1)-positive patients with rheumatoid arthritis. However, the detailed mechanisms behind this invalidation are unclear. Additionally, it remains unclear whether T-SPOT.TB® or QuantiFERON-TB (QFT) is more useful in HTLV-1-positive patients with rheumatic disease (RD).MethodAmong all of the HTLV-1-positive RD patients who visited our department between August 2012 and December 2022, 44 patients who were screened using T-SPOT.TB® were included in the analysis. QFT testing was performed in 33 of the 44 patients, and the results were compared with that of T-SPOT.TB®. Furthermore, we performed a culture experiment mimicking T-SPOT.TB® using peripheral blood mononuclear cells (PBMCs) obtained from HTLV-1-positive patients with RD. Additionally, T-cell subsets with autonomous product IFN-γ were analyzed using a flow cytometer.ResultsOf the included patients, 13 (29.5%) were invalid for T-SPOT.TB® because of the increased number of negative control spots. The median HTLV-1 proviral load in the invalid group was higher than that in the valid group (2.45 vs. 0.49 copies/100 PBMCs, respectively, p = 0.002). QFT was performed in all 33 patients, including 13 patients who were invalid in T-SPOT.TB®. The main source of IFN-γ production was CD8+ T-cells in the T-SPOT.TB® mimic experiment. Furthermore, Tax-expressing CD4+ T-cells and Tax-specific cytotoxic CD8+ T-cells were more frequently observed in patients with invalid results than in patients with valid results. CD4+ T-cell depletion in the T-SPOT.TB® mimic experiment reduced the population of IFN-γ producing CD8+ T cells.ConclusionT-SPOT.TB® may be invalidated by the interaction between Tax-expressing CD4+ T-cells and cytotoxic CD8+ T-cells. Moreover, HTLV-1-associated immune reactions due to contact between these cells may be unlikely to occur in QFT using whole blood. Therefore, our results reveal the superiority of QFT over T-SPOT.TB® as a screening test for LTBI in HTLV-1-positive patients with RD.

Introduction Human immunodeficiency virus (HIV) and human T cell leukemia/lymphoma virus type 1 (HTLV-1) share similar routes of transmission and both target T cells. HTLV-1 may negatively affect the course of disease in people living with HIV, but previous evidence is conflicting. Therefore, we aimed to investigate the prevalence of HIV/HTLV-1 co-infection, routes of transmission, and patients’ CD4+ counts. Material and methods 184 HIV-positive individuals were recruited for this cross-sectional study from the Counseling Center for Behavioral Diseases of Imam Khomeini Hospital in Tehran. Serum samples were analyzed using enzyme-linked immunosorbent assay (ELISA) for anti-HTLV-1. Results The mean age of participants was 40.12 ± 11.6 years, and all cases were negative for HTLV-1 infection. Participants were diagnosed on average about 78 months (6 years) ago, and the mean CD4+ count of the participants was 669.22 cells/µl (SD = 284.2). Using ELISA screening, none of the participants from Tehran in various age groups showed concurrent HTLV-1 infection (0 percent). Conclusions Co-infection with HTLV-1 is negligible in HIV-infected patients in Tehran, Iran. Our data also showed that the most common route of HIV transmission among our study subjects was hetero­sexual contact (56.4%).

Objectives. The HTLV-1 infection persists for life, remaining as asymptomatic viral reservoirs in most patients, ensuring the chain of transmission, but around 4% develop adult T-cell leukemia/lymphoma (ATLL). HTLV-1 is an oncogenic retrovirus that transforms CD4+ T lymphocytes and deregulates the lymphoproliferative pathways that contribute to the development of ATLL. To achieve cell transformation, most oncogenic retroviruses use proto-oncogene capture transduction, with proviral integration disrupting the expression of tumor suppressors or proto-oncogenes. The aim. We conducted this study on the prevalence of HTLV-1 infection in blood donors to expand the HTLV-1 database, assess the risk of transmission via blood products, as well as evaluate the risk of persistent infection or development of neoplastic diseases in HTLV-1 carriers. Materials and methods. This is a cross-sectional study of blood donors of all categories. For this study, 265 blood donors were recruited at the Centre National de Transfusion Sanguine in Brazzaville. After testing for HTLV-1 antibodies by ELISA, proviral DNA was extracted from all ELISA-positive samples for detection by nested PCR, followed by RT qPCR using specific primers p53 and c-myc for gene expression. Results. 20/265 were positive for anti-HTLV-1 antibody, 5 donors were positive for proviral DNA. The prevalence of HTLV-1 was 1.8%. All HTLV-1-positive donors were male (1.8%), with a positive correlation (p = 0.05); the 1.1% of positive donors were regular, with the majority aged between 31 and 45 years (1.5%), and concubine donors were the most frequent (1.1%). All samples showed normal expression of the p53 and c-myc genes. Conclusion. The prevalence, though low, remains a serious problem. No abnormal p53 or c-myc gene expression was detected in HTLV-1-positive donors, which could mean that none of the T lymphocytes in these donors had been transformed by HTLV-1.

Abstract Introduction Human T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection. Material and Methods The study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3β), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software. Results While there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3β, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs. Conclusion HTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis.

BackgroundHTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors.Patients and methodsWe recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification.ResultsWe found that systemic IL-6 was positively correlated with both age (r = 0.50, p

Introduction: Human T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection. Material and Methods: The study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3β), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software. Results: While there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3β, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs. Conclusion: HTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) carriers may develop adult T-cell leukemia (ATL), or HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The evidence is limited regarding other diseases potentially associated with HTLV-1, such as HTLV-1-associated autoimmune diseases. We summarized the available information on complications associated with HTLV-1 infection. Previous studies showed that HTLV-1 carriers have an increased incidence of collagen diseases including Sjögren's syndrome, as well as dysthyroidism, diabetes mellitus, and atherosclerosis. Furthermore, cognitive deficits are observed in asymptomatic carriers and in symptomatic carriers who develop HAM/TSP. It is hypothesized that altered immunoregulation occurs as a result of persistent HTLV-1 infection. A systematic review and meta-analysis demonstrated that HTLV-1 infection itself has an adverse impact on overall survival. ATL alone cannot entirely explain the adverse impact of HTLV-1 infection on overall mortality, because the incidence is low, and therefore HTLV-1-associated diseases as a whole may contribute to the inferior clinical outcome. However, there are insufficient data to determine the causal relationship between HTLV-1 infection and each complication. While non-cancerous events linked to HTLV-1 infection are not fatal, they are likely to reduce quality of life. Large prospective studies should be conducted by international collaborators. [ABSTRACT FROM AUTHOR]

Human T-cell lymphotropic virus type 1 (HTLV-1) is linked to two debilitating diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy tropical spastic paraparesis (HAM/TSP), which are prevalent in various parts of the world, including the Alborz province in Iran. Understanding the prevalence and evolutionary relationships of HTLV-1 infections in these endemic areas is of utmost importance. In the realm of phylogenetic studies, long terminal repeat (LTR) region of HTLV-1 stands out as highly conserved, yet more variable compared to other gene segments. Consequently, it is the primary focus for phylogenetic analyses. Additionally, trans-activator of transcription (Tax), an oncoprotein, holds a pivotal role in the regulation of gene expression. This cross-sectional study delved into the phylogenetic analysis of HTLV-1 among individuals in Alborz province of Iran. To confirm infection, we amplified partial sequence LTR (PLTR) and HTLV-1 bZIP factor (PHBZ). For phylogenetic analysis, we sequenced the full sequence LTR (FLTR) and full Tax sequence (FTax). The FLTR and FTax sequences underwent analysis using BioEdit, and phylogenetic trees were constructed using MEGA-X software. Out of the roughly 15,000 annual blood donors in Alborz, 19 samples tested positive for HTLV-1, indicating a 0.13% HTLV-1 positivity rate among blood donors. Furthermore, the HTLV-1 virus prevalent in the Alborz province belongs to subtype A (cosmopolitan) subgroup A. The findings revealed that while mutations were observed in both the LTR and Tax genes, they were not significant enough to bring about fundamental alterations. Despite positive selection detected in three Alborz isolates, it has not led to mutations affecting Tax function and virulence. [ABSTRACT FROM AUTHOR]

The human T-cell leukemia virus type 1 (HTLV-1) was first described in 1980. It is spread in highly endemic regions in the world, such as the Southwestern part of Japan, sub-Saharan Africa and South America, Caribbean, Middle East, and Australo-Melanesia regions. HTLV-1 causes adult T cell leukemia and is associated with many inflammatory conditions, most notably HTLV-1-associated myelopathy/tropic spastic paraparesis. HTLV-2, first isolated in 1982, was recognized as a common infection in intravenous drug users, but a clear association with disease remains elusive. The first estimate of HTLV-1-positive individuals worldwide, in 1993, was around 10-20 millions. Due to the lack of global population-based prevalence studies, this is considered an underestimate at the moment. Furthermore, HTLV-1 prevalence in Europe is impacted by changing migration flows. Particularly, no data on HTLV-1 prevalence in the general population in Italy are available. Here, we report a systematic literature review of studies conducted in Italy on HTLV-1/2 from 1980 to 2023. Based on the criteria we adopted a total of 426 publications were found (64 reviews, 99 epidemiological, and 263 translational studies). The contents of some representative publications are summarized and discussed. Moreover, an approximate estimation of about 26,000 HTLV-1 positive foreigners living in Italy was obtained from updated data of foreigners from each single country officially registered as resident in Italy and from data on HTLV-1 prevalence among the general population in the corresponding countries. [ABSTRACT FROM AUTHOR]

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-1β 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. [ABSTRACT FROM AUTHOR]

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia--lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis. [ABSTRACT FROM AUTHOR]

The 30th workshop of the HTLV European Research Network (HERN) was held in Madrid on September 15–16, 2023. Over fifty researchers from Europe and America convened for a two-day conference to update and discuss basic science, epidemiology, clinical management and therapeutics for patients with HTLV-1 infection. Scientific topics addressed included new estimates for HTLV-1 in Europe; impact of antenatal screening on mother-to-child HTLV-1 infections; new insights into the molecular epidemiology of HTLV-1; reports of elite controllers for HTLV-1 infection; role of antiretrovirals as HTLV-1 pre-exposure prophylaxis; and prospects for a HTLV-1 vaccine. The group agreed to submit a formal request to WHO for increasing the global surveillance and awareness of HTLV-1. This viral infection is a potentially life-threatening, neglected condition with neither treatment nor vaccine. At this time, expanding HTLV-1 screening is the most effective way to reduce viral dissemination. [ABSTRACT FROM AUTHOR]

Adult T cell leukemia/lymphoma is a malignancy with a poor prognosis caused by human T lymphocyte virus type 1 (HTLV-1) infection. Tax and HBZ are two major viral proteins that may be involved in oncogenesis by disrupting apoptosis. Because Bcl-xL plays an integral role in the anti-apoptotic pathway, this study examines the interaction between host apoptosis and oncoproteins. We investigated 37 HTLV-1-infected individuals, including 18 asymptomatic and 19 adult T cell leukemia/lymphoma (ATLL) subjects. mRNA was extracted and converted to cDNA from peripheral blood mononuclear cells, and then gene expression was determined using TaqMan q-PCR. Moreover, the HTLV-1 proviral load (PVL) was also measured using a commercial absolute quantification kit (Novin Gene, Iran). Data analysis revealed that the mean of TAX, HBZ, and PVL was significantly higher among the study groups (ATLL and carrier groups p = .003, p = .000, and p = .002 respectively). There was no statistical difference in Bcl-xL gene expression between the study groups (p = .323). It is proposed that this anti-apoptotic pathway may not be directly involved in the development of ATLL lymphoma. Bcl-xL, TAX, HBZ gene expression, and PVL can be utilized as prognostic markers. [ABSTRACT FROM AUTHOR]

Despite the accuracy of confirmatory tests for the diagnosis of human T cell lymphotropic virus (HTLV), inconclusive or false-negative results still occur when diagnosing human T cell lymphotropic virus type 2 (HTLV-2)-positive patients. The goal of this study was to evaluate the sensitivity and accuracy of a confirmatory immunoassay, the Multi-HTLV assay. A total of 246 plasma samples were tested by real-time polymerase chain reaction (qPCR) and used to calculate the sensitivity and typing accuracy of the Multi-HTLV assay. Of the 246 plasma samples, 127 were positive for human T cell lymphotropic virus type 1 (HTLV-1), 112 were positive for HTLV-2, and 7 were positive for both HTLV-1 and HTLV-2. Thereafter, the nonparametric Mann–Whitney U test was used to calculate the concordance between the qPCR test and Multi-HTLV assay in 12 samples with discrepant and inconclusive qPCR results. The Multi-HTLV assay showed high performance in identifying HTLV-1 and HTLV-2 with sensitivities of 97% [95% confidence interval (CI): 0.92–0.98] and 94% (0.87–0.96), respectively. However, due to typing performance (98% for HTLV-1 and 94% for HTLV-2), it had 95% agreement with positive HTLV-1 qPCR results (95% CI: 90.07–97.81) and 86% (78.04–91.01) of HTLV-2 qPCR results were positive. Moreover, this test was able to recognize 80% of indeterminate samples and all HTLV-2 positive samples that showed false-negative qPCR results. Our findings, derived from a substantial number of HTLV-positive samples, underscore the inherent reliability and feasibility of the Multi-HTLV assay, regardless of the molecular testing facilities. Furthermore, the distinctive multiparametric nature of this assay, combined with its straightforward procedural execution, introduces novel perspectives for analyzing specific serological profiles in each patient, as well as the potential for immunological monitoring of disease progression. [ABSTRACT FROM AUTHOR]

Persistent viruses are hard to be eradicated, even using effective medications, and can persist for a long time in humans, sometimes regardless of treatment. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and human T cell lymphotropic virus infections, the most common in our era, are still a challenge despite the increased knowledge about their biology. Most of them are highly pathogenic, some causing acute disease or, more often, leading to chronic persistent infections, and some of the occult, carrying a high risk of morbidity and mortality. However, if such infections were discovered early, they might be eradicated in the near future with effective medications and/or vaccines. This perspective review points out some specific characteristics of the most important chronic persistent viruses. It seems that in the next few years, these persistent viruses may have control by vaccination, epidemiological strategies, and/or treatment. [ABSTRACT FROM AUTHOR]

Human T-cell Leukemia Virus type 1 (HTLV-1) is a human retrovirus responsible for leukaemia in 5 to 10% of infected individuals. Among the viral proteins, Tax has been described as directly involved in virus-induced leukemogenesis. Tax is therefore an interesting therapeutic target. However, its 3D structure is still unknown and this hampers the development of drug-design-based therapeutic strategies. Several algorithms are available that can be used to predict the structure of proteins, particularly with the recent appearance of artificial intelligence (AI)-driven pipelines. Here, we review how the structure of Tax is predicted by several algorithms using distinct modelling strategies. We discuss the consequences for the understanding of Tax structure/function relationship, and more generally for the use of structure models for modular and/or flexible proteins, which are frequent in retroviruses. [ABSTRACT FROM AUTHOR]

In this study, we aimed investigated the differential gene expression profiles of samples from uninfected individuals (control group) and study groups of asymptomatic human T-lymphotropic virus 1 (HTLV-1) carriers and patients with HTLV-1-associated myelopathy (HAM) by exploratory RNA sequencing (RNA-Seq) analysis. The gene expression profiles of individuals in the asymptomatic group were represented by 3 genes, most associated with cell cycle regulation. The gene expression profiles of individuals in the HAM group were represented by 12 genes, the majority of which are associated with the immune response. The HLA-A gene and the non-coding RNA LINC02470 were upregulated in the asymptomatic and HAM groups. The HLA-DQB1 and HLA-C genes were downregulated in the asymptomatic and HAM groups. In this pilot study, although limited in terms of methodological rigor, we showed differential gene expression profiles in different clinical groups of HTLV-1 infection. However, further studies are needed to confirm these findings.