Search

To investigate a 12-year historical series (2006-2017) of human T-cell lymphotropic virus (HTLV)-positive blood donations from Fundação Hemominas, Minas Gerais, Brazil, an observational retrospective study was performed to evaluate data of blood donor candidates who were screened for HTLV-1/2 by enzyme-linked immunosorbent assay or chemiluminescence assays and confirmed by Western blot. We analyzed 3 309 716 blood donations covering 2006-2017 that were extracted from the institutional database. In a total of 3 308 738 donations that have complete algorithm tests, the global frequency of HTLV-positive donations was 0.012%. The seroprevalence in first-time blood donors was 28.82/100 000 donors; 0.95/100 000 donations were HTLV-positive in repeat blood donors. The frequency of HTLV-seropositive females was significantly higher than males (odds ratio = 1.85, p 0.001) in first-time donors. The median age of HTLV-positive first-time and repeat donors was similar (36 and 32 years, respectively). First-time donors ≥41 years had higher odds to be infected. There was a clear tendency of decline in the HTLV-positive donations in the period analyzed, going from 19.26/100 000 donations to 8.50/100 000 donations. The increase in the proportion of repeat donors over the period analyzed (from 23% in 2006 to 67% in 2017) must be the principal factor that contributed to this drop. Our results showed a continuous decline in the frequency of HTLV-positive donations from Minas Gerais, Brazil throughout 12 years and emphasize the importance of having a high rate of repeat donors in blood centers to reduce the residual risk of transfusion-transmitted infections.

A risk-based approach to the testing of blood donations for Human T-Lymphotropic Virus (HTLV) should include an assessment of blood donation seroepidemiology. The objectives of the present study were to determine the proportion of HTLV positive units in Irish blood donations, and subsequently, to estimate the current risk of transfusion transmitted HTLV (TT-HTLV).Over 3 million donations screened between 1996 and 2020, were included in the study (n = 3,666,253). Factors considered in the assessment of TT-HTLV risk included: (I) HTLV seropositivity, (ii) probability of a leucodepletion failure, and (iii) the HTLV testing strategy.Six HTLV positive donations were detected throughout the study period, all of them in previously unscreened blood donors (0.000164%; n = 6/3,666,253), 3 of whom had donated prior to the introduction of HLTV antibody testing. On average 0.11% of manufactured blood components assessed, failed to satisfy the leucodepletion quality assurance criteria of less than 1 × 10This is the first report on the proportion of HTLV positive in Irish blood donations (1996-2020) and will be used to inform blood donation screening policy in Ireland. Evidence is provided for recommending a selective HTLV donor screening algorithm in Ireland that is accompanied by a robust framework for continued surveillance of leucodepletion failure rate.

Transfusion-transmitted viruses count among the greatest threats to blood safety. In Argentina, current laws oblige testing all donated blood for the presence of antibodies against human T-cell lymphotropic viruses 1 and 2 (HTLV-1/2). In endemic zones of the country, a high rate of seronegative HTLV-1 individuals with clear evidence of infection because of symptoms and/or presence of tax sequences of HTLV-1 and/or IgG anti-Tax antibodies has been recently described. Migration from endemic to nonendemic zones of Argentina is very frequent.During a 1-year period, in the blood bank of Córdoba city, we performed molecular screening of all donors who were born in or arose from endemic zones for HTLV-1/2 in Argentina and neighbouring countries.By screening 219 bp of HTLV-1/2 tax gene, 0.6% (2/317) of the blood donors proved to be positive for HTLV-1 tax sequence. One of the donors presented anti-Tax antibodies, demonstrating the transcriptional activity of the tax gene, and the other donor was also positive for LTR and pol gene sequences. The HTLV-1 genetic analysis of the LTR sequence determined that it belonged to the Cosmopolitan subtype HTLV-1aA.These findings suggest potential limitations of some currently approved screening assays for HTLV-1 detection applied in some donor populations and the possibility of an HTLV-1 seronegative carrier state with the potential for silent transmission by blood.

In the United Kingdom, organ donors/recipients are screened for evidence of human T-cell leukaemia virus type-1 and type-2 (HTLV-1/2) infections. Since the United Kingdom is a low prevalence country for HTLV infections, a screening assay with high sensitivity and specificity is required. Samples with repeat reactivity on antibody testing are sent to a reference lab for confirmatory serological and molecular testing. In the case of donor screen, this leads to delays in the release of organs and can result in wastage. We aim to assess whether a signal/cut-off (S/CO) ratio higher than the manufacturer's recommendation of 1.0 in the Abbott Architect antibody assay is a reliable measure of HTLV-1/2 infection.We conducted a 5 year retrospective analysis of 7245 patients from which 11 766 samples were tested on the Abbott Architect rHTLV I/II assay. Reactive samples (S/CO 1) were referred for confirmatory serological and molecular detection (Western Blot and proviral DNA) at UK Health Security Agency, (formerly PHE, Colindale), the national reference laboratory. Electronic, protected laboratory and hospital patient databases were employed to collate data.A total of 45 patients had initially reactive samples. 42.2% (n = 19/45) had an S/CO ratio 20, with HTLV infection confirmed in n = 18/19 and indeterminate confirmatory results in n = 1/19. No samples with an S/CO ratio4 (48.9%, n = 22/45) or 4-20 (8.9%, n = 4/45) had positive confirmatory results on subsequent confirmatory testing.Samples with an S/CO20 likely represent a true HTLV-1/2 infection. Reactive samples with an S/CO 4 were unlikely to confirm for HTLV infections. Interpretation of these ratios can assist clinicians in the assessment of low reactive samples and reiterates the need for faster access to confirmatory testing.

It is obvious that genetic differences, including mutations and polymorphisms, can play an important role in viral infections. In this case-control study, which included 81 human T-cell leukemia virus type 1 (HTLV-1) asymptomatic carriers (AC) and 162 healthy controls (HC), the rs4143815 polymorphism of PDL1 gene was investigated. This polymorphism is the site of miR-570 binding and it can influence immune system responses. The rs4143815 polymorphism was evaluated by allele-specific polymerase chain reaction (AS-PCR) and the proviral load levels by quantitative real-time PCR (q PCR). The results demonstrated that the C allele (P = 0.027) and the CC genotype (P = 0.031) of rs4143815 polymorphism was significantly higher in the AC group than in the HC group, also the proviral load in the AC group with the C allele (P = 0.020) was significantly higher. Thus, the rs4143815 polymorphism can play a vital role in HTLV-1 infection.

Central Australia is a human T cell leukaemia virus type 1c (HTLV-1c) endemic region which has the highest incidence of chronic kidney disease (CKD) in Australia. Factors associated with HTLV-1 seropositivity among Aboriginal Australian adults with CKD receiving haemodialysis (HD) were determined. A retrospective observational study of Aboriginal adults (≥ 18 years) who were receiving regular haemodialysis (HD) at the two main dialysis units in Alice Springs, 1st December 2010 to 31st December 2015. Demographic and clinical data prior to commencing HD were extracted from hospital records from first presentation to Alice Springs Hospital (ASH) to HD commencement and associations were determined using logistic regression. Among 373 patients receiving HD, 133 (35.9%) were HTLV-1 infected. Identifiable factors associated with HTLV-1 status included increasing age, male gender and diabetes prior to HD. The odds of diabetes mellitus was significantly higher among patients with HTLV-1 (aOR 2.76, 95% CI 1.19, 6.39; p=0.017). More than one fifth of participants had an acute kidney injury, the risk of which was increased among those with a previous blood stream infection (aOR 3.02, 95% CI 1.71, 5.34, p

Peripheral T‐cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T‐cell leukemia/lymphoma (ATLL) and peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) are common in Japan. ATLL is an incurable T‐cell malignancy induced by human T‐cell lymphotropic virus type 1 (HTLV‐1). The global genomics of ATLL can be summarized as alterations involving T‐cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral‐mediated T‐cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV‐1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL‐related genes is identified in a part of HTLV‐1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL‐NOS is a heterogeneous disease type of T‐cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL‐NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL., Coexistence of CD28 fusions is highly characteristic of young Japanese adult T‐cell leukemia/lymphoma (ATLL). This suggests the existence of heterogeneity of ATLL.

Adult T-cell leukemia (ATL) is a life-threatening malignant neoplasm of CD4+ T cells resulted from human T-cell leukemia virus type I (HTLV-I). Tax1 protein of HTLV-I can induce malignant proliferation of T-cells through modulating the expression of growth factors such as platelet-derived growth factor (PDGF). Here, we aimed to investigate the proviral load (PVL) of HTLV-I in ATL, and also to evaluate mRNA expression of B chain of PDGF and PDGF-β receptor in ATL patients and HTLV-I-infected healthy carriers. To this end, peripheral blood mononuclear cells (PBMCs) were isolated by using Ficoll-Histophaque density centrifugation. The mean of HTLV-I PVL in ATL patients (42759 ± 15737 copies/104 cells [95% CI, 9557-75962] was significantly (p = 0.01) higher than that in healthy carries (650 ± 107 copies/104 cells [95% CI, 422-879], respectively. The HTLV-I PVL in ATL patients exhibited a significant correlation with PBMC count (R= 0.495, p= 0.001). The mRNA expression of Tax, B chain of PDGF, and PDGF-β receptor genes was significantly higher in healthy patients than patients with ATL. In conclusion, the expression of the canonical PDGFβ and its receptor, and their correlation with Tax expression cannot be a suitable indicator and/or prognostic factor for progression of ATL in HTLV-I carriers. This article is protected by copyright. All rights reserved.

Human T-cell lymphotropic virus type 1 (HTLV-1), the causative agent of adult T-cell leukaemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is endemic in sub-Saharan Africa (SSA) and poses a high morbidity and mortality risk. Its prevalence in the general population is poorly understood. The potential for prevention motivated us to do a systematic review and meta-analysis of population-based studies to estimate the prevalence of HTLV-1 in SSA.A comprehensive, no-limit search was conducted in EMBASE, PubMed, Web of Science and the Cochrane Library from their inception dates to March 2019. Population-based studies presenting data on HTLV-1 in sub-Saharan Africa were included. Pooled prevalence was estimated using a random-effects meta-analysis.A total of 21 studies were included, representing 42 297 participants. The pooled HTLV-1 seroprevalence was 3.19% (95% CI 2.36-4.12%) with variations across year of study. Prevalence of HTLV-1 positively correlated with year of study (β = 0.0036, P = 0.007). Participants from Central, Western and Southern Africa had a seroprevalence of 4.16% (95% CI 2.43-6.31%), 2.66% (95% CI 1.80-3.68%) and 1.56% (95% CI 0.48-3.15%), respectively.Our findings suggest that HTLV-1 infection is a public health concern in SSA and highlight the need to implement effective preventive programmes and interventions aimed at reducing the burden of this common yet neglected infection.PRÉVALENCE DANS LA POPULATION DU VIRUS T-LYMPHOTROPIQUE HUMAIN DE TYPE 1 (HTLV-1) EN AFRIQUE SUBSAHARIENNE: OBJECTIF: Le virus lymphotropique T humain 1 (HTLV-1), l'agent causal de la leucémie T de l'adulte/lymphome (ATL) et la myélopathie associée à HTLV-1/paraparésie spastique tropicale (HAM/TSP), est endémique en Afrique subsaharienne (ASS) et présente un risque élevé de morbidité et de mortalité. Sa prévalence dans la population générale est mal comprise. Le potentiel de prévention nous a incité à procéder à une revue systématique et à une méta-analyse des études basées sur la population afin d'estimer la prévalence du HTLV- 1 en ASS. MÉTHODES: Une recherche approfondie et sans limite a été effectuée dans EMBASE, PUBMED, Web of Science et dans la Cochrane Library, depuis leur création jusqu’à mars 2019. Des études basées sur la population présentant des données sur HTLV-1 en ASS ont été incluses. La prévalence poolée a été estimée à l'aide d'une méta-analyse à effet aléatoire. RÉSULTATS: Un total de 21 études ont été incluses, représentant 42.297 participants. La séroprévalence poolée du HTLV-1 était de 3,19% (IC95%: 2,36% à 4,12%), avec des variations au cours de l'année de l’étude. La prévalence du HTLV-1 était corrélée positivement avec l'année d’étude (bêta = 0,0037, p = 0,007). Les participants d'Afrique centrale, de l'Ouest et Australe présentaient une séroprévalence de 4,16% (IC95%: 2,43% à 6,31%), de 2,66% (IC95%: 1,80% à 3,68%) et 1,56% (IC95%: 0,48% à 3,15%), respectivement. CONCLUSIONS: Nos résultats suggèrent que l'infection au HTLV-1 est une préoccupation de santé publique en ASS et soulignent la nécessité de mettre en œuvre des programmes et des interventions préventives efficaces visant à réduire la charge de cette infection commune mais négligée.

The diagnosis of human T -cell leukemia virus type 1 (HTLV-1) infection in Japan is usually performed by serological testing, but the high rate of indeterminate results from western blotting makes it difficult to assess the infection accurately. Nucleic acid tests for HTLV-1 and/or HTLV-2 are used to confirm infection with HTLV-1 and/or HTLV-2 and are also used for the follow-up of HTLV-1 related diseases. To prepare a highly sensitive method that can discern infection with HTLV-1 and HTLV-2, a multiplex quantitative polymerase chain reaction (qPCR) by large-scale primer screening was developed. Sensitivity and specificity were evaluated by serial dilution of cell lines and by testing with known clinical samples. The resulting multiplex qPCR can detect about four copies of HTLV-1 provirus per 105 cells. Moreover, HTLV-1 provirus could be detected in 97.2% (205 of 211) of HTLV-1 seropositive clinical samples. These sensitivities were sufficiently high compared with the methods reported previously. Also, all the HTLV-2 seropositive clinical samples tested were found to be positive by this method (three of three). In conclusion, this method can successfully and simultaneously detect both types of HTLV-1 and HTLV-2 provirus with extremely high sensitivity.

We estimate the fractions of cancer attributed to infections in Africa in 2018. The number of new cancer cases occurring was taken from Globocan2018 with some additional estimations based on data from African population-based registries. Population attributable fractions were calculated using prevalence of infection and relative risk in exposed vs. nonexposed. The greatest share of infection-associated cancers is due to the human papillomaviruses (12.1% of all cancers in Africa and 15.4% in sub-Saharan Africa [SSA]); of these, cervical cancer is by far the most common. Kaposi sarcoma-associated herpesvirus is responsible for 3.1% of all cancers in Africa, the hepatitis viruses (B and C) for 2.9% and Helicobacter pylori for 2.7% (non-Cardia Gastric cancer and primary gastric lymphomas). Two percent of cancers are attributable to the Epstein-Barr virus, Schistosoma haematobium increases the risk of bladder cancer resulting in 1.0% of all cancers. HIV-related NHL and squamous cell carcinoma of the conjunctiva account for 0.6% of cancers. Altogether 24.5% of cancers in Africa and 28.7% in SSA are due to infectious agents. Infections are by far the most common cancer risk factor for cancer in Africa-the traditional risk factors (smoking, alcohol and unhealthy diet) probably cause only one in eight cancers in Africa. Prevention should focus on those infectious diseases preventable through vaccination (HPV and hepatitis B) which could reduce two-thirds of the burden. Helicobacter pylori and schistosomiasis are treatable with antibiotics and praziquantel, with a potential reduction of one in eight infection-associated cancers.

Objective Human T cell lymphotropic virus 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8+ T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV‐1‐specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL‐2 and IL‐15 stimulate memory CD8+ T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu‐Mikβ1, a humanized monoclonal antibody directed toward the IL‐2/IL‐15 receptor β‐chain (IL‐2/IL‐15Rβ: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL‐15 action. Methods Hu‐Mikβ1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu‐Mikβ1 were administered at 3‐week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV‐1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. Results There was no significant toxicity associated with Hu‐Mikβ1 administration in HAM/TSP patients. Saturation of CD122 by Hu‐Mikβ1 was achieved in five out of nine HAM/TSP patients. Administration of Hu‐Mikβ1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN‐γ expression, especially in HAM/TSP patients that achieved CD122 saturation. Interpretation The treatment with Hu‐Mikβ1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose‐related toxicity.

This narrative review, which is based on a systematic literature search following the PRISMA guidelines, provides a general overview of Human T-cell Lymphotropic Virus type 1 (HTLV-1) and associated diseases: Adult T-cell Leukaemia-Lymphoma (ATLL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in Latin America, focusing on epidemiology and prevention. Using the published information on HTLV-1, ATLL and HAM/TSP prevalence, we present comprehensive and accurate maps and tables, and developed an algorithm to assist in the prevention of HTLV-1 transmission through breastfeeding while considering socio-economic status. Latin America is an interesting scenario to study HTLV-1 because of the diverse origin of its population. Apart from the expected high prevalence in inhabitants of African ancestry, the presence of endemic foci affecting indigenous populations is particularly striking. ATLL prevention is the biggest challenge in this field. Most ATLL cases are transmitted through breastfeeding; thus, prevention methods to avoid ATLL in endemic countries have to be focused on this. In view of the high inequality in most Latin American countries, reduction in breastfeeding duration, freezing/thawing and pasteurisation of breastmilk can be suitable interventions in poor settings, considering that avoiding the risk of malnutrition and infant mortality must be the priority.Cette revue narrative, qui repose sur une recherche bibliographique systématique conforme aux recommandations de PRISMA, fournit un aperçu général sur le virus lymphotropique des lymphocytes T humaines de type 1 (HTLV-1) et les maladies associées: Le lymphome leucémique des cellules T d'adulte (ATLL)) et la myélopathie/paraparésie spastique tropicale (HAM/TSP) associée à HTLV-1 en Amérique latine, en se focalisant sur l’épidémiologie et la prévention. En utilisant les informations publiées sur la prévalence de HTLV-1, ATLL et HAM/TSP, nous présentons des cartes et des tableaux complets et précis et avons développé un algorithme pour aider à la prévention de la transmission du HTLV-1 par l'allaitement tout en tenant compte du statut socioéconomique. L'Amérique latine est un scénario intéressant pour l’étude de HTLV-1 en raison de la diversité des origines de sa population. Outre la forte prévalence escomptée chez les habitants de descendance africaine, la présence de foyers endémiques affectant les populations autochtones est particulièrement frappante. La prévention de l’ATLL est le plus gros défi dans ce domaine. La plupart des cas d’ATLL sont transmis par l'allaitement. Ainsi, les méthodes de prévention pour éviter l’ATLL dans les pays d'endémie doivent être concentrées sur cela. Compte tenu de la forte inégalité qui règne dans la plupart des pays d'Amérique latine, la réduction de la durée de l'allaitement, la congélation/décongélation et la pasteurisation du lait maternel peuvent constituer des interventions appropriées dans les milieux pauvres, tout en considérant que la priorité est d’éviter les risques de malnutrition et de mortalité infantile.

Background and objectives Currently, HTLV screening is not performed in South Africa (SA). This report describes an economic assessment (budget impact and cost-effectiveness) of implementing different HTLV screening strategies. Methods A modified version of the Alliance of Blood Operators risk-based decision-making framework was used to assess the risk and consequences of HTLV in the blood supply in SA. We developed a deterministic model of the cost and consequences of four screening strategies: none, universal, all donors once and first time donors only assuming a transfusion-transmission (TT) efficiency of 10% and a manifestation of clinical disease of 6%. Results Unscreened blood results in 3·55 symptomatic TT-HTLV cases and a total healthcare cost of Rand (R)3 446 950 (US Dollars (USD)229 800) annually. Universal screening would cost R24 000 000 (USD1 600 000) per annum and prevent 3·54 (99·8%) symptomatic TT-HTLV cases in the first year and 0·55 (98·4%) symptomatic TT-HTLV cases in the second year at a cost per TT-HTLV prevented of R6 780 000 (USD450 000) in year one and R43 254 000 (USD2 890 000) in year two. Screening all donors once would cost R16,200,000 (USD1 080 000) or R4 600 000 (USD306 000) per symptomatic TT-HTLV infection prevented in year one. Total costs decrease to R5 100 000 (USD340 000) in year 2 but the cost per TT-HTLV prevented increases to R10 700 000 (USD713 333). Conclusion This analysis contributed to the decision not to implement HTLV screening as the healthcare budget and particularly the budget for blood transfusion in SA is insufficient to provide appropriate treatment. Arguably, available resources can be more efficiently utilized in other healthcare programs.

Background China has not yet incorporated routine human T-lymphotropic virus (HTLV)-1/2 blood donor screening, even though HTLV has been reported in the southeastern coastal region. This study was conducted to investigate the prevalence of HTLV in five major regions across of China. Methods From January 2016 to December 2017, blood samples were collected in 20 blood centers located in different regions of China. These samples were screened for HTLV-1/2 antibodies using enzyme-linked immunosorbent assay (ELISA). If the test samples were reactive, the samples were confirmed with a western blot (WB) assay. If the results of WB were indeterminate, the donor was interviewed after a minimum lapse of 8 weeks. All follow-up samples from donors were tested for anti-HTLV-1/2 with ELISA and WB. Results There were 875,453 donor samples tested for anti-HTLV-1/2 by ELISA. In all, 365 samples tested negative, 22 samples tested positive by WB, and 14 samples with HTLV status undetermined due to being lost to follow-up. The prevalences were 11.09, 5.96, 3.16, 2.88 and 0.98 per 100,000 in Xiamen, Changsha, Beijing, Shenzhen, and Nanjing blood center, respectively. The prevalences were 0 per 100,000 for all 15 other blood centers. There was significant differences in the prevalence of HTLV in different regions of China (p = 0.0011). Conclusion In China, HTLV-1 confirmed positive donors are mainly from southeastern coastal areas. It may be necessary to conduct HTLV screening in these areas to reduce the risk of transfusion-transmitted HTLV.

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disease caused by human T‐cell leukemia virus type 1 (HTLV‐1). Multi‐agent chemotherapy can reduce ATL cells but frequently allows relapses within a short period of time. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) following chemotherapy is now a standard therapy for ATL in Japan as it can achieve long‐term remission in approximately one‐third of recipient ATL patients; however, it also has a risk of treatment‐related mortality. Allo‐HSCT often induces HTLV‐1 Tax‐specific cytotoxic T cells (CTL) as well as graft‐versus‐host (GVH) response in ATL patients. This observation led to development of a new therapeutic vaccine to activate Tax‐specific CTL, anticipating anti‐ATL effects without GVH response. The newly developed Tax‐DC vaccine consists of autologous dendritic cells pulsed with Tax peptides corresponding to CTL epitopes that have been identified in post‐allo‐HSCT ATL patients. In a pilot study of Tax‐DC therapy in three ATL patients after various initial therapies, two patients survived for more than 4 years after vaccination without severe adverse effects (UMIN000011423). The Tax‐DC vaccine is currently under phase I trial, showing a promising clinical outcome so far. These findings indicate the importance of patients’ own HTLV‐1‐specific T‐cell responses in maintaining remission and provide a new approach to anti‐ATL immunotherapy targeting Tax. Although Tax‐targeted vaccination is ineffective against Tax‐negative ATL cells, it can be a safe alternative maintenance therapy for Tax‐positive ATL and may be further applicable for treatment of indolent ATL or even prophylaxis of ATL development among HTLV‐1‐carriers.

Background and objectives In Canada, transfusion transmission risk of Human T-cell lymphotropic virus -I/II (HTLV) is addressed by universal leucoreduction and universal antibody testing. We aimed to estimate the risk with the current policy, if testing only first-time donors and if testing were stopped. Materials and methods Monte Carlo simulation was employed to estimate the proportion of red cell concentrate, random donor platelet and apheresis platelet units that would be released into inventory in each scenario (10 billion donors each). The model estimated the number of HTLV-positive donations not intercepted by testing, randomly assigned the number of HTLV particles/100 leucocytes using proportions from published data and randomly selected a postleucoreduction leucocyte count from quality control data. Units were considered infectious if ≥9 × 104 copies of HTLV provirus. Results With universal leucoreduction in place, the residual risk of releasing an HTLV potentially infectious unit with universal testing was 1 in 1·2 billion units (0, 1 in 55·9 million), with testing only first-time donors 1 in 7·1 million (0, 1 in 1·05 million) and with no testing 1 in 1·0 million (0, 1 in 178 600). The efficacy of leucoreduction was >99·5% (lower bound 95·7%) for all scenarios. Conclusion With universal leucoreduction in place, switching from universal testing to testing first-time donors would incur very low risk.

Human T-lymphotropic virus (HTLV), the first human retrovirus has been discovered which is known to cause the age-old assassinating disease HTLV-1 associated myelopathy. Cancer caused by this virus is adult T cell leukemia/lymphoma which targets 10-20 million throughout the world. The effect of this virus extends to the fact that it causes chronic disease to the spinal cord resulting in loss of sensation and further causes blood cancer. So, to overcome the complications, we designed a subunit vaccine by the assimilation of B-cell, cytotoxic T-lymphocyte , and helper T-lymphocyte epitopes. The epitopes were joined together along with adjuvant and linkers and a vaccine was fabricated which was further subjected to 3D modeling. The physiochemical properties, allergenicity, and antigenicity were evaluated. Molecular docking and dynamics were performed with the obtained 3D model against toll like receptor (TLR-3) immune receptor. Lastly, in silico cloning was performed to ensure the expression of the designed vaccine in pET28a(+) expression vector. The future prospects of the study entailed the in vitro and in vivo experimental analysis for evaluating the immune response of the designed vaccine construct.

miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

Human T-cell lymphoma virus (HTLV) has been associated with various disease types. Since the discovery of the virus in 1980, seven subtypes of the virus have been identified. HTLV is widespread and endemic in some regions, such as Japan, Africa, South America, and northeast Iran. This study aimed to identify HTLV-1 genotype and also to analyze the nucleotide sequence of the LTR region in three groups, including blood donors, HIV-1+ patients, and β-thalassemia patients. In this cross-sectional study, 2200 samples were collected from blood donors in Tehran (2000 samples), HIV-1+ patients (100 samples) and β-thalassemia patients (100 samples). All samples were screened for anti-HTLV-I&II antibodies by ELISA. Then, genomic DNA was extracted from repeatedly positive samples, and nested PCR was performed for both the TAX and LTR regions. Purified PCR products were sequenced and analyzed, and finally, a phylogenetic tree was constructed using Mega7 software. The prevalence of the anti-HTLV-I&II antibody among blood donors and HIV-1+ patients was 1.7% (34/2000) and 12% (12/100), respectively. The PCR results confirmed that 0.05% (1/2000) of blood donors, 5% (5/100) of HIV-1+ patients, and 8% (8/100) of β-thalassemia patients were HTLV-I positive. All sequences were matched to HTLV-1 subtype a, subgroup A. Our phylogenetic analysis revealed that all sequenced samples belong to the endemic clusters of Iran. HTLV-1 genotypes in all samples were similar in three groups and were derived from the strains, which had been previously reported from Iran (AF00300/Mashhad and KT190712.1/Sabzevar).

Background and Objectives Universal testing of blood donations for human T-cell lymphotropic virus (HTLV) in Australia may no longer be appropriate given the low prevalence of HTLV infection and the mitigating effect of universal leucodepletion for cellular components. This study aimed to determine the most appropriate HTLV testing strategy using the Risk-Based Decision-Making Framework for Blood Safety. Materials and Methods The risk of HTLV transfusion–transmission using three testing strategies (universal, new-donor and no testing) and cost-effectiveness of the first two strategies were assessed using adaptations of published mathematical models. Results The overall prevalence for 2004–2014 was three HTLV-positives per million donations. It was estimated that annually, universal testing incurred a cost of approximately AUD $3 million and prevented 83 HTLV-positive cellular components from being issued, and new-donor testing cost approximately $225 000 and prevented 81 components. The number of cases of transfusion-transmitted HTLV and HTLV-associated disease prevented per year by universal and new-donor testing was essentially equivalent. According to preset risk thresholds, the risk of transfusion–transmission was negligible for universal and new-donor testing, and minimal without testing. Conclusion Transfusion–transmission of HTLV is a minimal risk in Australia even without testing. However, any revision of testing strategy must consider not only risk and cost-effectiveness, but also stakeholder, ethical and regulatory perspectives. Considering all relevant criteria, new-donor testing is judged the optimal strategy because it is able to achieve almost the same outcomes as universal testing, at a fraction of the cost.

Adult T-cell leukemia/lymphoma (ATL) occurs in approximately 5% of individuals infected with human T-cell leukemia virus type 1 (HTLV-1). A high proviral load (PVL; more than four copies per 100 peripheral blood mononuclear cells (PBMCs) or 1.6 copies per 100 blood leukocytes) and being male are risk factors for ATL development. Whether anti-HTLV-1 antibody level is related to such risk is unknown. Here, PVL and antibody levels were examined using real-time PCR and other tests in 600 HTLV-1 positive screened Japanese blood donors to understand the relationship between PVL and antibody level in asymptomatic carriers and to gain insights toward better antibody testing for HTLV-1 infection. The 430 donors in whom proviral DNA was detected were considered as true positives for HTLV-1 infection. Among donors aged 40 years or older, more males than females had a PVL corresponding to more than 1.6% infected leukocytes, and an antibody titer below the median (P = 0.0018). In antibody tests using an HTLV-1 positive cell line or Env antigens there was a large discrepancy in antibody titer among 13 provirus-positive samples, probably suggesting that antibody-based screening tests should incorporate multiple HTLV-1 antigens, such as Gag and Env antigens.

Recruitment of leukocytes by chemokines and chemokine receptors to CNS plays a crucial role in the induction of inflammatory response in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In the present study, chemokine and chemokine receptors involved in trafficking of lymphocytes to the CNS were measured in HAM/TSP patients, HTLV-1 asymptomatic carriers (ACs), and healthy controls. The PVL, CCR6, and CXCR3 mRNA expression, and CXCL9 and CXCL10 protein levels were measured in all subjects. The PVL of HAM/TSP patients was higher than that of ACs (P = 0.02). CCR6 expression was higher in HAM/TSP patients and in ACs compared to the healthy controls (P = 0.005 and P = 0.04, respectively). A significant difference was observed in CCR6 expression when a combination of HAM/TSP patients and ACs were compared to the healthy individuals (P = 0.005). Furthermore, there was a significantly lower CXCR3 expression between HAM/TSP and control groups (P = 0.001), and between the ACs and healthy controls (P = 0.001). However, the increased CXCR3 expression in ACs compared to HAM/TSP patients was not significant. Furthermore, the CXCL10 protein levels in HAM/TSP patients was higher than in controls (P = 0.012), and CXCL9 protein levels was also higher in the HAM/TSP and ACs groups than in the controls (P = 0.001 and P = 0.004, respectively). In conclusion, it seems that decreased expression of CXCR3 and higher expression of CCR6 were associated with HTLV-1 infection, what indicate that these alterations may favor virus dissemination but not disease manifestation.

Aim Sarcoidosis is an autoimmune multiorgan granulomatosis disease with unknown origin. Some environmental factors such as viruses may induce the disease in genetically susceptible individuals. Human T cell lymphotropic virus type 1 (HTLV-1) can dysregulate the human immune system and the role of this virus in the pathogenesis of autoimmune diseases has been investigated and documented, such as in uveitis. In this study, we have focused on the seroprevalence of HTLV-1 in sarcoidosis in comparison to the normal population in the northeast of Iran, an endemic area for HTLV-1. Methods This cross-sectional study enrolled 125 patients with established sarcoidosis to evaluate the frequency of HTLV-1 and compare it with the normal population of Mashhad, Iran. Participants' blood samples were analyzed for HTLV-1 antibody by an enzyme-linked immunosorbent assay kit. Positive results were confirmed by polymerase chain reaction method. Finally, data were analyzed using SPSS 11. Results Among sarcoidosis patients 106 (84.8%) patients had a history of acute course and 19 (15.2%) had chronic sarcoidosis. Four percent of the patients versus 2.12% of the Mashhad population were HTLV-1 positive with no statistical difference (P = 0.201). In age- and sex-matched selected controls, 3.6% were HTLV-1 positive again with no statistical difference by sarcoidosis group (P = 0.52). There was no statistical difference between arthritis, erythema nodusom, uveitis, constitutional symptoms, abnormal chest radiography (parahilar lymphadenopathy) and computed tomography scan findings, respiratory symptoms, sex, the course of the sarcoidosis in HTLV-1 positive and negative sarcoidosis patients. Conclusion The frequency of HTLV-1 in 125 sarcoidosis patients was 4%. In comparison with prevalence of HTLV-1 in Mashhad, HTLV-1 seroprevalence did not show any significant difference.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Human T-cell lymphotrophic virus 1 (HTLV)-1 in the pre- and post-transplant period. HTLV-1 is an oncogenic human retrovirus rare in North America but endemic in the Caribbean and parts of Africa, South America, Asia, and Oceania. While most infected persons do not develop disease,5% will develop adult T-cell leukemia/lymphoma or neurological disease. No proven antiviral treatment for established HTLV-1 infection is available. The effect of immunosuppression on the development of HTLV-1-associated disease in asymptomatically infected recipients is not well characterized, and HTLV-1-infected individuals should be counseled that immunosuppression may increase the risk of developing HTLV-1-associated disease and they should be monitored post-transplant for HTLV-1-associated disease. Currently approved screening assays do not distinguish between HTLV-1 and HTLV-2, and routine screening of deceased donors without risk factors in low seroprevalence areas is likely to result in significant organ wastage and is not recommended. Targeted screening of donors with risk factors for HTLV-1 infection and of living donors (as time is available to perform confirmatory tests) is reasonable.

Background The natural history of human T-cell leukemia virus type 1 (HTLV-1), which causes adult T-cell leukemia (ATL) or HTLV-1 associated myelopathy, after liver transplantation is unclear. Methods We conducted a nationwide survey to investigate the impact of HTLV-1 status on living donor liver transplantation (LDLT) in Japan. We analyzed the cases of 82 HTLV-1-positive recipients and six HTLV-1-negative-before-LDLT recipients who received a hepatic graft from HTLV-1-positive donors. Results Adult T-cell leukemia developed in five recipients who ultimately died. Of these five, two received grafts from HTLV-1-positive donors and three from HTLV-1-negative donors. The 1-, 3-, and 5-year ATL development rates were 4.5%, 6.5%, and 9.2%, respectively. Fulminant hepatic failure as a pre-transplant diagnosis was identified as an independent risk factor for ATL development (P = 0.001). The 1-, 3-, and 5-year survival rates for HTLV-1-positive recipients who received grafts from HTLV-1-negative donors were 79.9%, 66.1%, and 66.1%, and from HTLV-1-positive donors were 83.3%, 83.3%, and 60.8%, respectively. The 1-year survival rate for HTLV-1-negative recipients who received grafts from HTLV-1-positive donors was 33.3%. Conclusions Fulminant hepatic failure is an independent risk factor for ATL development in HTLV-1-positive recipients. Grafts from HTLV-1-positive living donors can be transplanted into selected patients.

Infective dermatitis (ID) associated with Human T-cell leukemia virus type-1 (HTLV-1) is a rare form of severe superinfected eczema seen mostly in the Caribbean islands and Latin America. Although rapid response to antibiotic treatment is observed, patients should be monitored for development of complications associated with this retroviral infection, including T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Infective dermatitis is rarely seen in the United States and therefore may be under-recognized by physicians unfamiliar with this condition. Herein, we present an additional case report of an ID associated with HTLV-1 in an 11-year-old girl from Trinidad.

Background and Objectives The risk of transfusion-transmitted human T-lymphotropic virus type 1 infection (TT-HTLV-1) after prestorage leucocyte reduction (LR) remains unknown, as the proviral load in the blood component that would cause TT-HTLV-1 is undetermined. On the basis of the distribution of HTLV-1 proviral load among HTLV-1-sero-positive blood donors, we attempted to estimate the proviral load for transfusion-related infectivity. We also discuss the effectiveness of LR in preventing TT-HTLV-1. Materials and Methods The HTLV-1 proviral load in 300 HTLV-1-sero-positive blood donors was determined by real-time polymerase chain reaction analysis. The proviral load required for transfusion-related infectivity was estimated using historical TT-HTLV-1 frequency data from a retrospective study on patients who had received blood from HTLV-1-sero-positive blood donors and the distribution pattern of HTLV-1 proviral load among blood donors. Results HTLV-1 proviral loads ranged between

We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T-cell leukemia virus type 1 (HTLV-1) infection. In CD4(+) cells from peripheral blood, CADM1(-) CD7(+) (P), CADM1(+) CD7(dim) (D) and CADM1(+) CD7(-) (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV-1 carriers (AC) progress to indolent adult T-cell leukemia-lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4(+) cells and inverse long PCR (clonality analysis) of FACS-sorted subpopulations. Almost all AC with a high HTLV-1 proviral load (4 copies/100 cells) had a CADM1(+) (D + N) frequency of10%. AC with 25%CADM1(+) ≤ 50% contained expanded clones similar to smoldering-type ATL. In many patients in the 25%CADM1(+) ≤ 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering-type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high-risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long-term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category.

Recent advances in treatment for adult T-cell leukemia-lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon-α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5-year OS rates are 100% for both the smoldering-type and chronic-type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti-CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T-cell leukemia virus type-I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL.

Virological synapses (VS) increase cell-to-cell viral transmission and facilitate propagation of human immunodeficiency virus type 1 (HIV-1) and human T-cell leukaemia virus type 1 (HTLV-1). VS formation also plays a more general role in viral replication and dissemination. VS have been observed in vitro and ex vivo between uninfected T cells and T cells infected with HIV-1 or HTLV-1. In addition, dendritic cells (DC) infected with HIV-1 also play an important role in viral transmission to uninfected CD4+ T cells via VS formation. Recent studies revealed that several DC subsets are also infected with HTLV-1. These findings may help explain the rapid dissemination of both viruses within secondary lymphoid tissues in vivo. VS also explain, at least in part, why HIV-1 can propagate in the mucosal sites during sexual transmission. Furthermore, in the case of HTLV-1, VS can potentially explain some of the features of HTLV-1-associated dermatitis as infected T cells in the skin contribute to the pathogenesis of this condition.

The association between viruses and lymphomas has long been recognized; however, the pathophysiological phenomena behind this relationship are unclear, and have been the object of intense research. Although our understanding of such mechanisms is slowly improving, much is still left to learn. With the recent advances in cancer biology, a diversity of biological pathways and novel targets and agents have been described in patients with haematological malignancies and successfully put into clinical practice. Clear examples are rituximab and brentuximab vedotin in patients with B cell lymphomas and Hodgkin lymphoma respectively. The main purpose of this review is not only to succinctly summarize what we know regarding the pathogenesis and pathophysiology of virally induced lymphomas and to describe the current practices in terms of diagnosis of treatment of such lymphomas, but also to provide a scientific rationale for the use of novel therapies that are likely to improve the outcomes of patients with these conditions.

It has been more than 30 years since the discovery of human T‐lymphotropic virus type 1 (HTLV‐1), the first human retrovirus identified. Human T‐lymphotropic virus type 1 infects 15–20 million people worldwide causing two major diseases: adult T‐cell leukemia/lymphoma and HTLV‐1‐associated myelopathy/tropical spastic paraparesis. Human T‐lymphotropic virus type 1 establishes several decades of latent infection, during which viral–host interaction determines disease segregation. This review highlights non‐structural proteins that are encoded on the viral genome and manage latent infection. Latent infection is a key in HTLV pathology, so that effective inhibition of these proteins might lead to successful disease management.

Pulmonary involvement has been identified in human T-lymphotropic virus type I (HTLV-I) carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the relationship between HTLV-I infection and lung disease is poorly understood. The occurrence of HTLV-I-specific immune responses in the lungs of patients infected with HTLV-I with pulmonary involvement was investigated. The frequency of HTLV-I-specific CD8+ cells and the amount of HTLV-I proviral DNA were determined in bronchoalveolar lavage fluid cells and peripheral blood mononuclear cells (PBMCs) from five patients with HAM/TSP and one HTLV-I carrier who had pulmonary involvement. HTLV-I-specific CD8+ cells were detected by flow cytometry using human leukocyte antigen/antigen complex multimers. The analysis of bronchoalveolar lavage fluid revealed lymphocytosis in five of six patients. HTLV-I provirus was detected in the bronchoalveolar lavage fluid cells of all patients, and the proviral load in these cells was comparable to that in PBMCs. The frequency of HTLV-I-specific CD8+ cells in the bronchoalveolar lavage fluid cells was 5.1 times higher than that in PBMCs. Immunohistochemically, clusters formed by HTLV-I-specific CD8+ cells were detected in lung tissue by in situ tetramer staining. No samples were available from patients infected with HTLV-I without lung disorders. Whether accumulation of CD8+ cells is specific to patients with pulmonary involvement remains unclear. These results indicate that HTLV-I-specific CD8+ cells accumulate and HTLV-I-infected cells exist in the lungs of patients infected with HTLV-I with pulmonary involvement.

Human T-cell leukemia virus type-1 (HTLV-1), a major source of adult T-cell leukemia and related diseases, is endemic to southwestern Japan. Mother-to-infant transmission via breast milk is an important route of infection, and establishing programs to prevent such transmission requires exact figures on the HTLV-1 prevalence rate and the number of carriers. Therefore, the seroprevalence of HTLV-1 among 1,196,321 Japanese first-time blood donors from 2006 to 2007 was investigated. A total of 3,787 of such donors were confirmed to be positive for anti-HTLV-1 antibody. By applying a fitness curve to the age ranges outside the blood donor age range, the present number of HTLV-1 carriers covering ages from 0 to 99 years was estimated to be at least 1.08 million in Japan; this value was 10% lower than that reported in 1988. The adjusted overall prevalence rates were estimated to be 0.66% and 1.02% in men and women, respectively. The peak in carrier numbers was found among individuals in their 70s, which is a shift from the previous peak observed in the 1988 database among individuals in their 50s. Carriers were distributed not only in the endemic southwestern region of Japan, but throughout the country, particularly in the greater Tokyo metropolitan area. By applying population projections, it was calculated that the carrier number will decrease by half in the next two decades; however, the carrier population will age over that interval, meaning that the age of patients with adult T-cell leukemia will also be higher.

A high human T-cell lymphotropic virus type 1 (HTLV-1) proviral load is described in HTLV-1-associated diseases, especially HAM/TSP. However, the cut-off value to define high levels of HTLV-1 proviral load is not well established. 281 HTLV-1-infected patients from the HTLV reference center in Salvador, Brazil, were followed from 2005 to 2008. Patients were classified as asymptomatic, possible-, probable-, and definite-HAM/TSP, in accordance with diagnostic criteria proposed by De Castro-Costa et al. (2006): AIDS Res Hum Retroviruses 22:931-935. HTLV-1 proviral load was determined using real-time PCR. A receiver operator characteristic (ROC) curve was constructed using only asymptomatic individuals and definite-HAM/TSP patients. The ROC curve was used to predict the proviral load level that differentiates these two groups. Out of 281 patients, 189 were asymptomatic and 92 were diagnosed with HAM/TSP (22 possible, 23 probable, 47 definite). The mean HTLV-1 proviral load was higher in possible- (89,104 ± 93,006 copies/106 PBMC), -probable (175,854 ± 128,083 copies/106 PBMC), and definite-HAM/TSP patients (150,667 ± 122,320 copies/106 PBMC),when compared to asymptomatic individuals (27,178 ± 41,155 copies/106 PBMC) (P < 0.0001). A comparison of all HAM/TSP groups showed the highest proviral loads in probable-HAM/TSP patients, yet the differences in mean values were not statistically significant. The ROC curve suggested a value of 49,865 copies/106 PBMC, with 87% sensitivity (95% CI » 74-95) and 81% specificity (95% CI » 75-86), as the best proviral load cut-off point to differentiate definite HAM/TSP patients from asymptomatic individuals. HTLV-1 proviral loads are higher in groups of infected patients with eurological symptoms and may represent a relevant biological marker of disease progression.

Few studies have specifically examined defective provirus in asymptomatic human T-lymphotropic virus Type 1 (HTLV-1) carriers and its relation to proviral DNA loads (PVLs). To assess the significance of defective provirus in asymptomatic carriers, we examined PVLs in peripheral blood mononuclear cells of 208 asymptomatic HTLV-1 carriers. The mean PVLs determined using primers for the pol region were less than that for the pX region in these carriers. Analysis of seven carriers with high PVLs for the pX region but lower PVLs for the pol region showed that four had single nucleotide polymorphisms of proviral genomes for the pol region and three had HTLV-1-infected cells with defective provirus. Three carriers with defective provirus showed high PVLs at their initial screens, and PVLs increased after a 10- to 12-year interval in two carriers. Southern blot assay showed clonal expansion of HTLV-1-infected cells, and the predominant clones changed during the observation period. These data suggest that although HTLV-1-infected cells with defective provirus may have a growth advantage, the predominant clones of HTLV-1-infected cells do not always survive for many years in asymptomatic carriers.

HTLV infection appears to be more common among renal transplant candidates than in the related general population. HTLV-1-associated diseases may occur in carriers who are transplanted but there is insufficient evidence to confirm whether these occur more frequently as a result of the associated immunosuppression. Consequently, pre-existing HTLV-1 infection should not be considered a contra-indication to transplantation. The risk of transmission of HTLV-1 through solid organ transplantation from a confirmed infected donor is unknown. There are anecdotes of multiple infections from a single donor. Biologically due to the significant volume of blood and the lack of storage, transmission would be expected to be higher than following blood transfusion. The rate of subsequent disease is unknown, but there are now 11 reports of HAM and 2 of ATL occurring within 4 years of transplantation associated infection. There are insufficient data to know whether the time from infection to onset of disease and the rate of progression differ from transmission through other routes, but early onset and rapid progression is a concern. Responses to enhanced immunosuppression for the treatment of HAM are variable. The risk of HTLV-1 associated disease in exchange for a life-saving major organ transplantation from an infected donor might be considered worth taking by some HTLV-1 uninfected patients. Peri-transplantation antiretroviral prophylaxis with zidovudine and raltegravir is biologically sound but therapeutically unproven. The risks related to HTLV-1 infection appear to preclude the use of any other tissue. All transplant donors should be screened for HTLV-1 infection regardless of perceived risk.

Adult T-cell leukemia (ATL) is an aggressive malignancy of activated CD4(+) T cells associated with human T-cell leukemia virus type I (HTLV-I) infection. No conventional chemotherapy regimen has appeared successful in patients with ATL, thus establishing effective therapy is urgently required. In some cases, ATL tumor cells express CD30 on the cell surface, therefore, a therapy with mAb against CD30 would be beneficial. To investigate the effect of CD30-mediated therapy on ATL, we assessed SGN-30, a chimeric anti-CD30 mAb, and SGN-35, a monomethyl auristatin E-conjugated anti-CD30 mAb, in vitro and in vivo. Three HTLV-I-infected cell lines were co-cultured with SGN-30 or SGN-35, and the growth-inhibitory effects on the HTLV-I-infected cells were evaluated using an in vitro cell proliferation assay and cell cycle analysis. SGN-30 and SGN-35 showed growth-inhibitory activity against the HTLV-I-infected cell lines by apoptosis and/or cell growth arrest in vitro. To further investigate the effects of SGN-30 and SGN-35 on HTLV-I-infected cells in vivo, we used NOD/SCID mice subcutaneously engrafted with HTLV-I-infected cells. Both mAbs significantly inhibited the growth of HTLV-I-infected cell tumors in the NOD/SCID murine xenograft models. These data suggest that CD30-mediated therapy with SGN-30 or SGN-35 would be useful for patients with ATL.

Human T-lymphotropic virus type 1 (HTLV-1) is the agent of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may occur in >5% of patients during their lifetime. HTLV-1-infection causes disturbances in the immune system, and the viral load may also play an important role in the pathogenesis of HAM/TSP. Some cytokines are involved in the pathogenesis of this disorder. We have determined IL-2, IL-4, IL-10, IL-12 p70, IFN-gamma and TNF-alpha production among HTLV-1-infected subjects from our HTLV-out Clinic in Institute of Infectious 'Emilio Ribas' in Sao Paulo city, Brazil. PBMC obtained from healthy controls (n = 32), asymptomatic HTLV-1 carriers (n = 68) and HAM/TSP patients (n = 44) were grown in the absence and in the presence of phytohaemagglutinin (PHA), and the supernatants' fluids were measured for cytokines production. IL-2 levels were increased in the asymptomatic HTLV-1 carriers, and IFN-gamma was increased in both groups of patients (asymptomatic HTLV-1 carriers and more significantly among HAM/TSP patients). IL-4, IL-10, TNF-alpha and IL-12 p70 levels were not significantly increased on both groups of patients, as compared with controls. The major finding of this study is that IFN-gamma was an important cytokine for the HAM/TSP pathogenesis. Therefore, immune modulation of IFN-gamma may be critical to treat of HAM/TSP patients.

We evaluated whether risk of non-Hodgkin lymphoma (NHL), particularly adult T-cell leukemia/lymphoma (ATL) related to human T-lymphotropic virus (HTLV) infection was associated with 63 single nucleotide polymorphisms (SNPs) from 38 candidate genes. The 395 NHL cases registered in Jamaica were matched by age, sex, calendar-year and HTLV serostatus to 309 controls from the same population. Interleukin 13 (IL13) Ex4+98A>G SNP (rs20541) was associated with decreased NHL risk (OR(AG/AA) = 0.62,95% CI = 0.44-0.87, p = 0.006), as was vascular cell adhesion molecule-1, VCAM1 Ex9+149G>A SNP (rs1041163) (OR(CT) = 0.77, 95% CI = 0.54-1.10, OR(CC) = 0.35, 95% CI = 0.16-0.76, p-trend = 0.007). Both results were stronger in analyses restricted to ATL cases and HTLV-positive controls, suggesting a role for these genes in ATL etiology (IL13 OR(AG/AA) = 0.54, 95% CI = 0.36-0.84, p = 0.005; VCAM1 OR(CT) = 0.65, 95% CI = 0.42-1.01, OR(CC) = 0.20, 95% CI = 0.08-0.54, p-trend = 0.001). Confirmation of these results in Caribbean and other populations is needed.

Background Infective dermatitis (ID) is a rare dermatologic condition of childhood that has been linked to human T-cell lymphotropic virus type 1 (HTLV-1). Objective To analyze the clinical and laboratory features associated with adult-onset ID linked to HTLV-1. Methods From December 1995 to December 2007, four patients with ID were followed in the dermatology outpatient clinic of the “Hospital das Clinicas” of the University of Sao Paulo Medical School, Sao Paulo, Brazil. Epidemiologic data were collected and dermatologic examination was performed. Patients were submitted to histopathologic, hematologic, virologic, and immunologic investigations. Results All patients had a diagnosis of ID according to previously established criteria, despite being adults. HTLV-1 infection was demonstrated by enzyme-linked immunosorbent assay, Western blotting assays, and polymerase chain reaction. The male to female ratio was 1 : 3 and the median age at diagnosis was 42 years. The cutaneous manifestations were erythematous, scaly, and crusted lesions in all patients, and ichthyosis in three of the four cases. Histopathologic study showed lymphocytic epidermotropism in two cases. The median proviral load was 281 copies/10,000 peripheral blood mononuclear cells. Immunodeficiency was not observed in any case. The therapies used were antimicrobials, corticosteroids, and phototherapy. Conclusions Although many authors have considered ID to be a form of childhood dermatitis, we have described four cases that fulfilled the major criteria for ID, except for onset in adulthood.

The development of HTLV-1 associated clinical manifestations, such as TSP/HAM and ATLL, occur in 2-4% of the infected population and it is still unclear why this infection remains asymptomatic in most infected carriers. Recently, it has been demonstrated that HTLV uses the Glucose transporter type 1 (GLUT1) to infect T-CD4(+) lymphocytes and that single nucleotide polymorphisms (SNP) in the GLUT1 gene are associated with diabetic nephropathy in patients with diabetes mellitus in different populations. These polymorphisms could contribute to a higher GLUT1 protein expression on cellular membrane, facilitating the entry of HTLV and its transmission cell by cell. This could result in a higher provirus load and consequently in the development of TSP/HAM. To evaluate the role of GLUT1 gene polymorphisms in the development of TSP/HAM in HTLV-1 infected individuals, the g.22999G > T, g.15339T > C and c.-2841A > T sites were analyzed by PCR/RFLP or sequencing in 244 infected individuals and 102 normal controls. The proviral load of the HTLV-1 infected patients was also analyzed using Real Time Quantitative PCR. Genotypic and allelic frequencies of the three sites did not differ significantly between controls and HTLV-1 infected individuals. There was no difference in genotypic and allelic distributions among patients as to the presence or absence of HTLV-1 associated clinic manifestations. As regards the quantification of the provirus load, we observed a significant reduction in the asymptomatic individuals compared with the oligosymptomatic and TSP/HAM individuals. These results suggest that g.22999G > T, g.15339T > C, and c.-2841A > T SNP do not contribute to HTLV-1 infection nor to the genetic susceptibility of TSP/HAM in Brazilian HTLV-1 infected individuals.

Human T-cell leukemia virus type-1 (HTLV-1)-specific T-cell immunity, a potential antitumor surveillance system in vivo, is impaired in adult T-cell leukemia (ATL). In this study, we aimed to clarify whether the T-cell insufficiency in ATL is present before the disease onset or occurs as a consequence of the disease. We investigated T-cell responses against Tax protein in peripheral blood mononuclear cells (PBMCs) from individuals at earlier stages of HTLV-1-infection, including 21 asymptomatic HTLV-1 carriers (ACs) and four patients with smoldering-type ATL (sATL), whose peripheral lymphocyte count was in normal range. About 30% of samples tested showed clear Tax-specific interferon (IFN)-γ producing responses. Proviral loads in this group were significantly lower than those in the other less-specific response group. The latter group was further divided to two subgroups with or without emergence of Tax-specific responses following depletion of CC chemokine receptor 4 (CCR4)+ cells that contained HTLV-1-infected cells. In the PBMCs with Tax-specific responses, CD8+ cells efficiently suppressed HTLV-1 p19 production in culture. The remaining group without the emergence of Tax-specific response after CCR4+ cell-depletion included at least two sATL and one AC samples, which spontaneously produced HTLV-1 p19 in culture, where tetramer-binding, Tax-specific cytotoxic T-lymphocytes were either undetectable or unresponsive. Our results indicated that HTLV-1-specific T-cell responsiveness widely differed among HTLV-1 carriers, and that impairment of HTLV-1-specific T-cell responses was observed not only in advanced ATL patients but also in a subpopulation at earlier stages, which was associated with insufficient control of HTLV-1. (Cancer Sci 2009; 100: 481–489)

The natural history of human T-lymphotropic virus type I (HTLV-I) has been shown to differ markedly by geographic area. The differences include contrasting patterns of risk of adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may be due in part to differences in host immune response to infection. To characterize variations in host immunity across populations, we compared serologic immune marker patterns in HTLV-I-endemic populations in Japan and Jamaica. We matched 204 participants with archived blood from the Miyazaki Cohort Study (Japan) and the Food Handlers Study (Jamaica)-i.e., 51 HTLV-I-positive ("carriers") and 51 HTLV-I-negative individuals ("noncarriers") from each population-by age, sex and blood collection year. We compared plasma concentrations of markers of T-cell-mediated (antigen-specific) and nonspecific immunity using regression models and correlation coefficients. Compared to Jamaican HTLV-I noncarriers, Japanese noncarriers had higher covariate-adjusted mean levels of T-cell activation markers, including antibody to Epstein-Barr virus nuclear antigen-1 (reciprocal titer 27 vs. 71, respectively, p=0.005), soluble interleukin-2 receptor-alpha (477 vs. 623 pg/mL, p=0.0008) and soluble CD30 (34 vs. 46 U/mL, p=0.0001) and lower levels of C-reactive protein (1.1 vs. 0.43 microg/mL, p=0.0004). HTLV-I infection was associated with activated T-cell immunity in Jamaicans but with diminished T-cell immunity in Japanese persons. The observed population differences in background and HTLV-I-related host immunity correspond closely to the divergent natural histories of infection observed among HTLV-I carriers in Japan and Jamaica and corroborate a role for host immune status in the contrasting patterns of ATL and HAM/TSP risk.

The objectives of the study were to describe the introduction of testing blood donations for antibodies to human T-cell lymphotropic virus (anti-HTLV) and to determine the risk of HTLV potentially infectious donations entering the UK blood supply. The rationale for testing was based on (i) evidence of transmission through transfusion in the UK, (ii) the serious nature of HTLV I-associated morbidity and (iii) evidence of infection in UK blood donors. From mid-2002, all blood donations made at UK blood centres were tested in pooled samples using Abbott-Murex HTLV I/II GE 80/81 enzyme immunoassay (EIA). Surveillance data were used to calculate the incidence and prevalence of anti-HTLV and derive estimates of risk. Between August 2002 and December 2006, 106 donations were confirmed positive for anti-HTLV (95 anti-HTLV I and 11 anti-HTLV II). Prevalence was 10-fold higher among donations from new donors than repeat (4.0 and 0.42 per 100 000 donations), and only one repeat donor had evidence of seroconversion. The risk of an HTLV I potentially infectious donation entering the UK blood supply was estimated at 0.11 per million donations (95% confidence interval 0.06 to 0.18). The current very low observed incidence and prevalence among blood donors reflect the very low estimated risk of an HTLV I-positive donation entering the UK blood supply. A change in either the epidemiology of HTLV in UK blood donors or the length of the window period of the test should prompt further review of the risk and a reassessment of anti-HTLV testing in the UK.

To determine the seroprevalence of HTLV-1 in Brazil, and to review the virus molecular epidemiology in this Amazon population (Rio Branco-Acre), 219 blood donors were screened for HTLV-1. Only one case of infection (0.46% seroprevalence) was detected during July 2004 screening at the Acre Hospital Foundation (FUNDACRE). Neighbor-joining and Maximum Likelihood phylogenetic analyses of two (n = 2) complete LTR region sequences were performed with the PAUP* software. Since the HTLV-1 envelope surface (gp46) and transmembrane (gp21) glycoproteins are important for virus fitness, three envelope glycoproteins sequences (n = 3) were analyzed using the Prosite tool to determinate potential protein sites. Phylogenetic analysis demonstrated that the new isolate described in this study, and the unpublished LTR strain described in a previous report belong to the Transcontinental subgroup of the Cosmopolitan subtype, inside the Latin American cluster. A similar result was obtained when submitting, to the Automated Genotyping System, three LTR partial sequences from a previous study of the seroprevalence of HTLV-1 in the same Amazon population. In all analyzed env sequences, the potential protein site was found: two PKC phosphorylation sites at amino acid (aa) positions 310-312 and 342-344, one CK2 phosphorylation site at 194-197aa, three N-glycosylation sites at 222-225aa, 244-247aa and 272-275aa, and a single N-myristylation site at 327-338aa. In conclusion, potential protein sites described in HTLV-1 gp46 and gp21 confirm the presence of conserved sites in the HTLV-1 envelope proteins, likewise phylogenetic analysis suggests a possible recent introduction of the virus into North Brazil.

The seroprevalence rate of human T-lymphotropic virus (HTLV) among the Korean blood donor population was studied to determine whether screening for HTLV should be implemented. A total of 15,173 serum samples collected from June to July 2006 at five Blood Centers which are located closely to Japan geographically, where the prevalence of HTLV is known to be high, were tested. Serological screening was done by a chemiluminescence method. Samples reactive repeatedly on serological screening were confirmed further by Western blot, line immunoassay, nested polymerase chain reaction and sequencing of proviral DNA. Six samples tested reactive with the serological assay showing a reactive rate of 0.004%. Among the six samples, one sample was confirmed as HTLV-1 positive, giving a confirmed reactive rate of 0.007%. Based on the results of this study, an extended study will be conducted to evaluate whether introduction of HTLV screening is necessary in Korea. J. Med. Virol. 80:1864–1867, 2008. © 2008 Wiley-Liss, Inc.