The history of the Japanese Society for Neuro-infectious Diseases: Foundation, objectives, and legacy.

The Japanese Research Group for Neuro-infectious Diseases was founded in August 1996, and by 2004 it had evolved into the Japanese Society for Neuro-infectious Diseases. The Society focuses on neuroinfectious conditions (e.g., encephalitis/encephalopathy, myelitis, and meningitis), providing a venue for academic presentations and exchanges. Clinical guidelines for major neurological infectious diseases are also published by the Society, in order to meet the social demands of each era. Although the threat of herpes simplex encephalitis has declined due to acyclovir's introduction, the frequency of encephalitis or peripheral neuropathy caused by varicella-zoster virus is increasing. In Japan, prion disease, human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy (HAM), subacute sclerosing panencephalitis (SSPE), and progressive multifocal leukoencephalopathy (PML) are designated as intractable diseases. The incidence of prion disease is 1.8/1,000,000 individuals, with the sporadic type accounting for 80%. Prion disease is fatal, and effective medications are awaited. HAM's prevalence is ~3/100,000 individuals, with a male-to-female ratio of 1:2-3. HAM is common in western Japan, including Kyushu and Okinawa. The prevalence of PML is rising with the spread of both immunosuppressive therapy for transplantation and treatment for multiple sclerosis. From late 2019 through 2020, the world faced a global outbreak of coronavirus disease 2019 (COVID-19) due to virus mutations, and the threat of new mutations persists. Close attention should be paid to the emergence of new neurological infections that could arise from abnormal weather patterns and/or a decline in immune function due to aging.

Impact and economic analysis of human T-cell lymphotropic virus type 1 (HTLV-1)-targeted antenatal screening, England and Wales, 2021.

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) is a neglected virus that can cause severe disease and be transmitted from mother to child through breastfeeding. Avoidance of breastfeeding prevents 80% of vertical transmission. The United Kingdom (UK) is currently assessing whether HTLV-1-targeted antenatal screening should be implemented.AimWe aimed to assess the impact and cost-effectiveness of a targeted programme to prevent HTLV-1 vertical transmission in England and Wales.MethodsWe estimated the number of pregnant women who have high risk of HTLV-1 infection based on their or their partner's country of birth. With data from 2021, we used a mathematical model to assess cost-effectiveness of HTLV-1 antenatal screening. We also estimated the annual number of infant infections and the number that could be prevented with screening and intervention.ResultsWe estimate that ca 99,000 pregnant women in England and Wales have high risk of HTLV-1 infection. In the absence of screening, 74 (range: 25-211) HTLV-1 infections in infants would be expected to occur every year in England and Wales. Implementation of targeted screening would prevent 58 (range: 19-164) infant infections annually. The intervention is effective (incremental 0.00333 quality-adjusted life years (QALY)) and cost-saving (GBP -57.56 (EUR -66.85)).ConclusionOur findings support implementation of HTLV-1 targeted antenatal screening to reduce vertical transmission from mothers to infants in the UK.

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.

Human T-lymphotropic virus 1/2 infection among prisoners of a major penitentiary complex of Goiás State, Central-West Brazil.

Introduction: Studies on human T-lymphotropic virus 1/2 (HTLV-1/2) infection are scarce in incarcerated population. Therefore, this study estimated the prevalence of HTLV-1/2 infection among prisoners of the major penitentiary complex of Goiás State, Central-West Brazil, comparing it with available data from other Brazilian regions. Methods: A cross-sectional study was conducted with 910 prisoners of the major penitentiary complex in the State of Goiás, Central-West Brazil. All participants were interviewed, and their serum samples were tested for anti-HTLV-1/2 using an enzyme-linked immunosorbent assay (ELISA; Murex HTLV-I + II, DiaSorin, Dartford, UK). Seropositive samples were submitted for confirmation by a line immunoassay (INNO-LIA HTLV I/II, Fujirebio, Europe N.V., Belgium). Results: The majority of participants were males (83.1%), between 25 and 39 years old (56.1%; mean age: 31.98 years), self-reported brown ethnicity (56.2%) and reported 9 years or less of formal education (41.4%). Most reported using non-injectable illicit drugs and various sexual behaviors that present risk for sexually transmitted infections (STIs). The prevalence of anti-HTLV-1/2 was 0.33% (95% CI: 0.07-0.96), HTLV-1 (0.22%) and HTLV-2 (0.11%). The two HTLV-1 seropositive prisoners reported high-risk sexual behaviors, and the HTLV-2 seropositive individual was breastfed during childhood (> 6 months) by her mother and three other women. Conclusion: These data revealed a relatively low seroprevalence of HTLV-1/2 in prisoners in Central-West Brazil, and evidence of HTLV-1 and HTLV-2 circulation in the major penitentiary complex of Goiás State. Given the prevalence of high-risk sexual behaviors, there is a crucial need to intensify education and health programs in prisons to effectively control and prevent HTLV-1/2 and other STIs.

Prevalence of human T-cell lymphotropic virus-1/2 in Canada over 33 years: A unique contribution of blood donors to public health surveillance.

OBJECTIVES: Estimate HTLV-1/2 (human T-cell lymphotropic viruses) prevalence in Canadian blood donors and the association of demographic variables with infection and their corresponding risk factors. METHODS: First-time blood donors in all Canadian provinces (except Quebec) from 1990 to 2022 were included. Blood samples were tested for HTLV-1/2 by enzyme-linked immunoassay, confirmed by Western blot. Multivariable logistic regression with year, age group, sex, region, neighbourhood material deprivation, and ethnocultural composition indices predicted HTLV-1/2. Since 2005, all HTLV-1/2-positive donors (cases) were invited to participate in a risk factor interview, and 4 non-positive donors (controls per case) were matched for age, sex, and region. Case-control predictors of HTLV-1/2 were analyzed using logistic regression. RESULTS: There were 3,085,554 first-time donors from 1990 to 2022. HTLV-1/2 prevalence remained low (12 per 100,000 in 2022, 95% CI 6.4-23.5). The odds ratios predicting HTLV-1/2 were higher in females (2.0, 95% CI 1.5-2.6), older age groups (50 + ; 6.3, 95% CI 4.3-9.2), British Columbia and Ontario, those materially deprived (1.9, 95% CI 1.2-2.9), and those in ethnocultural neighbourhoods (7.5, 95% CI 3.2-17.3). Most HTLV-1/2 in Ontario was HTLV-1, whereas in British Columbia half were HTLV-2. Forty-three of 149 (28.8%) cases and 172 of 413 (41.6%) controls completed an interview. The strongest predictor of HTLV-1/2 in case-control analysis was birth in a high-prevalence country (OR 39.8, 95% CI 7.8-204.3) but about 50% of HTLV-1 and 90% of HTLV-2 were Canadian-born. CONCLUSION: HTLV-1/2 prevalence is low in blood donors. High-prevalence country of birth accounts for about half of HTLV-1; HTLV-2 positives are usually Canadian-born. HTLV-1/2 transmission likely occurs overseas and within Canada.

RéSUMé: OBJECTIFS: Estimer la prévalence des sous-types du virus T-lymphotrope humain (HTLV-1 et HTLV-2) dans le sang des donneurs de sang canadiens, et évaluer le lien avec des variables démographiques et des facteurs de risque donnés. MéTHODES: Cette étude a porté sur toutes les personnes ayant fait leur premier don entre 1990 et 2022 au Canada, sauf au Québec. Les échantillons de sang ont été soumis à un test immunoenzymatique, puis à un test Western Blot de confirmation. Les données ont été analysées au moyen de la régression logistique en utilisant comme indices l'année, la tranche d'âge, le sexe, la région, le quartier, la privation matérielle et la composition ethnoculturelle. Depuis 2005, tous les donneurs positifs au HTLV-1/2 (cas) ont été conviés à un entretien ayant pour but de déterminer leurs facteurs de risque, et quatre donneurs négatifs (cas-témoins) ont été appariés à chaque cas en fonction de l'âge, du sexe et de la région. Les facteurs de prédiction d'infection au HTLV-1/2 des cas-témoins ont été analysés au moyen de la régression logistique. RéSULTATS: Entre 1990 et 2022, le nombre de primodonneurs s'élevait à 3 085 554. La prévalence du HTLV-1/2 est demeurée faible (12,2 sur 100 000 en 2022, IC 95%: 6,4­23,5). Le rapport de cotes était plus élevé chez les femmes (2,0, IC 95% 1,5­2,6), chez les personnes de plus de 50 ans (6,3, IC 95% 4,3­9,2), en Colombie-Britannique et en Ontario, chez les personnes touchées par la privation matérielle (1,9, IC 95% 1,2­2,9) et chez les personnes vivant dans des quartiers ethnoculturels (7,5, IC 95% 3,2­17,3). La plupart des cas de HTLV-1/2 rencontrés en Ontario concernaient le HTLV-1, tandis qu'en Colombie-Britannique, la moitié des cas concernait le HTLV-2. Quarante-trois cas sur 149 (28,8 %) et 172 cas-témoins sur 413 (41,6 %) ont passé l'entretien. L'analyse des cas-témoins a révélé que le facteur de prédiction le plus important d'infection au HTLV-1/2 était le fait d'être né dans un pays à forte prévalence (RC 39,8, IC 95% 7,8­204,3); toutefois environ 50 % des cas-témoins de HTLV-1 et 90 % des cas témoins de HTLV-2 étaient nés au Canada. CONCLUSION: La prévalence du HTLV-1/2 est faible dans le sang des donneurs de sang. Pays de naissance à forte prévalence représente à peu près la moitié des cas de HTLV-1; les donneurs positifs au HTLV-2 la plupart du temps sont nés au Canada. La transmission du HTLV-1/2 survient probablement outre-mer et au Canada.

Human T-cell lymphotropic virus type 1 (HTLV-1) grip on T-cells: investigating the viral tapestry of activation.

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 (GSK3ß), 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 GSK3ß, 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.

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.

Prophylactic vaccination inducing anti-Env antibodies can result in protection against HTLV-1 challenge in macaques.

Human T cell leukemia/T-lymphotropic virus type 1 (HTLV-1) infection occurs by cell-to-cell transmission and can induce fatal adult T cell leukemia. Vaccine development is critical for the control of HTLV-1 transmission. However, determining whether vaccine-induced anti-Env antibodies can prevent cell-to-cell HTLV-1 transmission is challenging. Here, we examined the protective efficacy of a vaccine inducing anti-Env antibodies against HTLV-1 challenge in cynomolgus macaques. Eight of 10 vaccinated macaques produced anti-HTLV-1 neutralizing antibodies (NAbs) and were protected from an intravenous challenge with 108 HTLV-1-producing cells. In contrast, the 2 vaccinated macaques without NAb induction and 10 unvaccinated controls showed HTLV-1 infection with detectable proviral load after challenge. Five of the eight protected macaques were administered with an anti-CD8 monoclonal antibody, but proviruses remained undetectable and no increase in anti-HTLV-1 antibodies was observed even after CD8+ cell depletion in three of them. Analysis of Env-specific T cell responses did not suggest involvement of vaccine-induced Env-specific T cell responses in the protection. These results indicate that anti-Env antibody induction by vaccination can result in functionally sterile HTLV-1 protection, implying the rationale for strategies aimed at anti-Env antibody induction in prophylactic HTLV-1 vaccine development.

Increased H19/miR-675 Expression in Adult T-Cell Leukemia Is Associated with a Unique Notch Signature Pathway.

The Notch pathway is a key cancer driver and is important in tumor progression. Early research suggested that Notch activity was highly dependent on the expression of the intracellular cleaved domain of Notch-1 (NICD). However, recent insights into Notch signaling reveal the presence of Notch pathway signatures, which may vary depending on different cancer types and tumor microenvironments. Herein, we perform a comprehensive investigation of the Notch signaling pathway in adult T-cell leukemia (ATL) primary patient samples. Using gene arrays, we demonstrate that the Notch pathway is constitutively activated in ATL patient samples. Furthermore, the activation of Notch in ATL cells remains elevated irrespective of the presence of activating mutations in Notch itself or its repressor, FBXW7, and that ATL cells are dependent upon Notch-1 expression for proliferation and survival. We demonstrate that ATL cells exhibit the expression of pivotal Notch-related genes, including notch-1, hes1, c-myc, H19, and hes4, thereby defining a critical Notch signature associated with ATL disease. Finally, we demonstrate that lncRNA H19 is highly expressed in ATL patient samples and ATL cells and contributes to Notch signaling activation. Collectively, our results shed further light on the Notch pathway in ATL leukemia and reveal new therapeutic approaches to inhibit Notch activation in ATL cells.

PCBP1 interacts with the HTLV-1 Tax oncoprotein to potentiate NF-κB activation.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma. The HTLV-1 Tax constitutively activates nuclear factor-κB (NF-κB) to promote the survival and transformation of HTLV-1-infected T cells. Despite extensive study of Tax, how Tax interacts with host factors to regulate NF-κB activation and HTLV-1-driven cell proliferation is not entirely clear. Here, we showed that overexpression of Poly (rC)-binding protein 1 (PCBP1) promoted Tax-mediated IκB kinase (IKK)-NF-κB signaling activation, whereas knockdown of PCBP1 attenuated Tax-dependent IKK-NF-κB activation. However, Tax activation of HTLV-1 long terminal repeat was unaffected by PCBP1. Furthermore, depletion of PCBP1 led to apoptosis and reduced proliferation of HTLV-1-transformed cells. Mechanistically, PCBP1 interacted and co-localized with Tax in the cytoplasm, and PCBP1 KH3 domain was indispensable for the interaction between PCBP1 and Tax. Moreover, PCBP1 facilitated the assembly of Tax/IKK complex. Collectively, our results demonstrated that PCBP1 may exert an essential effect in Tax/IKK complex combination and subsequent NF-κB activation, which provides a novel insight into the pathogenetic mechanisms of HTLV-1.

Co-Infections and Superinfections between HIV-1 and Other Human Viruses at the Cellular Level.

Co-infection or superinfection of the host by two or more virus species is a common event, potentially leading to viral interference, viral synergy, or neutral interaction. The simultaneous presence of two or more viruses, even distantly related, within the same cell depends upon viral tropism, i.e., the entry of viruses via receptors present on the same cell type. Subsequently, productive infection depends on the ability of these viruses to replicate efficiently in the same cellular environment. HIV-1 initially targets CCR5-expressing tissue memory CD4+ T cells, and in the absence of early cART initiation, a co-receptor switch may occur, leading to the infection of naïve and memory CXCR4-expressing CD4+ T cells. HIV-1 infection of macrophages at the G1 stage of their cell cycle also occurs in vivo, broadening the possible occurrence of co-infections between HIV-1 and other viruses at the cellular level. Moreover, HIV-1-infected DCs can transfer the virus to CD4+ T cells via trans-infection. This review focuses on the description of reported co-infections within the same cell between HIV-1 and other human pathogenic, non-pathogenic, or low-pathogenic viruses, including HIV-2, HTLV, HSV, HHV-6/-7, GBV-C, Dengue, and Ebola viruses, also discussing the possible reciprocal interactions in terms of virus replication and virus pseudotyping.

HTLV-1-Associated Myelopathy (HAM) Incidence in Asymptomatic Carriers and Intermediate Syndrome (IS) Patients.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurological and clinical manifestations that do not meet diagnostic criteria for HAM. These conditions may later progress to HAM or constitute an intermediate clinical form: intermediate syndrome (IS), a mid-point between asymptomatic HTLV-1 carriers and those with full myelopathy. Thus, we determined the incidence of HAM cases in the HTLV-1-asymptomatic and IS patients, and the clinical/laboratory associated markers. A total of 204 HTLV-1-positive patients were included in this study, divided into two groups: Group 1, including 145 asymptomatic HTLV-1 subjects (ASY), and Group 2, including 59 patients with inflammatory clinical symptoms in more than three systems and a high proviral load (PVL). During a 60-month follow-up time, with the age ranging from 47 to 79 years, ten patients of the fifty-nine initially diagnosed as IS developed HAM (iHAM), and two patients of the initial 145 ASY developed HAM directly. Women were more prevalent in all groups. For the iHAM patients, the age ranged from 20 to 72 years, with a mean of 53 (±15 SD). Older age was associated with the development of HAM, higher PVL and IS; however, there was no any specific symptom or clinical sign, that was associated with risk for iHAM. In conclusion, IS cases could be an early phase of development of HAM. These findings show the presence of higher incidence probabilities in our cohort than previously reported.

An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis.

Autophagy and Unfolded Protein Response (UPR) can be regarded as the safe keepers of cells exposed to intense stress. Autophagy maintains cellular homeostasis, ensuring the removal of foreign particles and misfolded macromolecules from the cytoplasm and facilitating the return of the building blocks into the system. On the other hand, UPR serves as a shock response to prolonged stress, especially Endoplasmic Reticulum Stress (ERS), which also includes the accumulation of misfolded proteins in the ER. Since one of the many effects of viral infection on the host cell machinery is the hijacking of the host translational system, which leaves in its wake a plethora of misfolded proteins in the ER, it is perhaps not surprising that UPR and autophagy are common occurrences in infected cells, tissues, and patient samples. In this book chapter, we try to emphasize how UPR, and autophagy are significant in infections caused by six major oncolytic viruses-Epstein-Barr (EBV), Human Papilloma Virus (HPV), Human Immunodeficiency Virus (HIV), Human Herpesvirus-8 (HHV-8), Human T-cell Lymphotropic Virus (HTLV-1), and Hepatitis B Virus (HBV). Here, we document how whole-virus infection or overexpression of individual viral proteins in vitro and in vivo models can regulate the different branches of UPR and the various stages of macro autophagy. As is true with other viral infections, the relationship is complicated because the same virus (or the viral protein) exerts different effects on UPR and Autophagy. The nature of this response is determined by the cell types, or in some cases, the presence of diverse extracellular stimuli. The vice versa is equally valid, i.e., UPR and autophagy exhibit both anti-tumor and pro-tumor properties based on the cell type and other factors like concentrations of different metabolites. Thus, we have tried to coherently summarize the existing knowledge, the crux of which can hopefully be harnessed to design vaccines and therapies targeted at viral carcinogenesis.

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.

Human T-cell leukemia virus type 1 uses a specific tRNAPro isodecoder to prime reverse transcription.

Human T-cell leukemia virus type 1 (HTLV-1) is the only oncogenic human retrovirus discovered to date. All retroviruses are believed to use a host cell tRNA to prime reverse transcription (RT). In HTLV-1, the primer binding site (PBS) in the genomic RNA is complementary to the 3'-18 nucleotides (nt) of human tRNAPro The human genome encodes 20 cytoplasmic tRNAPro genes representing seven isodecoders, all of which share the same 3' 18-nt sequence but vary elsewhere. Whether all tRNAPro isodecoders are used to prime RT in cells is unknown. A previous study showed that a 3' 18-nt tRNAPro-derived fragment (tRFPro) is packaged into HTLV-1 particles and can serve as an RT primer in vitro. The role of this tRNA fragment in the viral lifecycle is unclear. In retroviruses, N1-methylation of the tRNA primer at position A58 (m1A) is essential for successful plus-strand transfer. Using primer-extension assays performed in chronically HTLV-1-infected cells, we found that A58 of tRNAPro is m1A-modified, implying that full-length tRNAPro is capable of facilitating successful plus-strand transfer. Analysis of HTLV-1 RT primer extension products indicated that full-length tRNAPro is likely to be the primer. To determine which tRNAPro isodecoder is used as the RT primer, we sequenced the minus-strand strong-stop RT product containing the intact tRNA primer and established that HTLV-1 primes RT using a specific tRNAPro UGG isodecoder. Further studies are required to understand how this primer is annealed to the highly structured HTLV-1 PBS and to investigate the role of tRFPro in the viral lifecycle.

Neurological aspects of HTLV-1 infection: symptoms in apparently asymptomatic carriers.

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.

A systematic review of immunosuppressive risk factors and comorbidities associated with the development of crusted scabies.

OBJECTIVES: Crusted scabies (CS, Norwegian scabies) is a severe form of scabies, characterized by hyper-infestation of Sarcoptes scabiei mites. CS is commonly associated with immunosuppression but is also reported in overtly immunocompetent individuals. We reviewed immunosuppressive risk factors and comorbidities associated with CS. METHODS: The National Library of Medicine (PubMed) database was reviewed for patient case reports of CS from January 1998 to July 2023. Two authors screened records for eligibility, extracted data, and one critically appraised the quality of the studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023466126. RESULTS: A total of 436 records were identified, of which 204 were included for systematic review. From these, 683 CS patients were included. CS impacted both genders equally. Adults (21-59 years) were more commonly affected (45.5%) compared to children (0-20 years, 21%). Corticosteroid use was the most prevalent immunosuppressive risk factor identified (27.7% of all cases). About 10.2% of reports were associated with HIV/AIDS, and 8.5% with HTLV-1 infection. 10.5% of patients were overtly immunocompetent with no known risk factors. Overall, 41 (6.0%) died, many subsequent to secondary bacteremia. CONCLUSION: This study represents the first systematic review undertaken on immunosuppressive risk factors associated with CS. This provides insights into trends of immunosuppression and mechanisms of CS development.

Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses.

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)-ß/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-ß/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-ß/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

"It's Only a Model": When Protein Structure Predictions Need Experimental Validation, the Case of the HTLV-1 Tax Protein.

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.

Ripasudil as a Potential Therapeutic Agent in Treating Secondary Glaucoma in HTLV-1-Uveitis: An In Vitro Analysis.

Human T-cell leukemia virus type 1 (HTLV-1), a virus that affects 5-10 million people globally, causes several diseases, including adult T-cell leukemia-lymphoma and HTLV-1-associated uveitis (HU). HU is prevalent in Japan and often leads to secondary glaucoma, which is a serious complication. We investigated the efficacy of ripasudil, a Rho-associated coiled coil-forming protein kinase inhibitor, in alleviating changes in human trabecular meshwork cells (hTM cells) infected with HTLV-1. HTLV-1-infected hTM cells were modeled in vitro using MT-2 cells, followed by treatment with varying concentrations of ripasudil. We assessed changes in cell morphology, viability, and inflammatory cytokine levels, as well as NF-κB activation. The results showed that ripasudil treatment changed the cell morphology, reduced the distribution of F-actin and fibronectin, and decreased the levels of certain inflammatory cytokines, such as interleukin (IL)-6, IL-8, and IL-12. However, ripasudil did not significantly affect NF-κB activation or overall cell viability. These findings suggest that ripasudil has the potential to treat secondary glaucoma in patients with HU by modulating cytoskeletal organization and alleviating inflammation in HTLV-1-infected hTM cells. This study lays the foundation for further clinical studies exploring the effectiveness of ripasudil for the treatment of secondary glaucoma associated with HU.