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.

Lived Experience of Human T-cell Leukemia Virus type-1 -Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): A Phenomenology Study.

Background: Human T-cell Leukemia Virus type-1 (HTLV-1) -associated myelopathy causes sufferers to experience changes in several aspects of their lives. Gaining a deeper understanding of these changes can help healthcare professionals improve care, enhance strategic decision-making, meet expectations, and manage patients effectively. However, there is no information about the experience and problems of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis in Iran. Therefore, this study aimed to explain the lived experience of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. Methods: This qualitative study used hermeneutic phenomenology in 2022 in Mashhad, Iran. Participants were selected using purposeful sampling. Data were collected through 21 semi-structured in-depth interviews with 20 eligible patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. The data were analyzed in MAXQDA/2020 using the six stages proposed by Van Manen. Results: The main concept of "Reduced self-sufficiency and social dignity" emerged from the narratives of the patients, which included three main categories "Disruption of desirable personal and social life", "reduced perception of role competencies", and "obligatory unpleasant lifestyle changes". Conclusion: HTLV-1-associated myelopathy/tropical spastic paraparesis slowly makes patients feel insufficient and causes a sense of degradation in dignity. The disease can fundamentally change personal and social life. Thus, due to its incurability and progressiveness, palliative care should be provided to them to live with dignity.

Effectiveness assessment of a home-based exercise intervention in mitigating HTLV-1 associated disabilities: A validation study.

To evaluate the effectiveness of a home exercise program called Home Exercise Booklet for People Living with Human T Lymphotropic Virus 1 (HTLV-1). This is a methodological study of content validation with expert judges. A questionnaire with a Likert scale was applied, containing 16 items referring to the content domain. Descriptive statistics were used to obtain the content validity index. In total, 46 judges participated, 24 physiotherapists (PG) and 22 professionals from other health areas specializing in methodological studies and HTLV-1 (EG). In the validation process, each evaluator judged the technology and scored their considerations. In the end, we obtained the following results for the Content Validity Index (CVI): PG CVI: 94.3%, GE CVI: 93.4%. Although the index was sufficient to consider the technology validated, modifications were made to the second and final version of the booklet, considering the judges' observations and suggestions, which we consider relevant. The technology proved to be valid for use with the target audience. The development and validation of this product provides support to help prevent functional decline in people living with HTLV-1; standardize guidelines for physiotherapy professionals who monitor these issues; start a home exercise program aimed at other comorbidities; open the possibility of creating and validating home exercise programs with other comorbidities.

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.

NF-κB1 deficiency promotes macrophage-derived adrenal tumors but decreases neurofibromas in HTLV-I LTR-Tax transgenic mice.

Human T-cell leukemia virus type I (HTLV-I) is an oncogenic virus whose infection can cause diverse diseases, most notably adult T-cell leukemia/lymphoma (ATL or ATLL), an aggressive and fatal malignancy of CD4 T cells. The oncogenic ability of HTLV-I is mostly attributed to the viral transcriptional transactivator Tax. Tax alone is sufficient to induce specific tumors in mice depending on the promotor used to drive Tax expression, thereby being used to understand HTLV-I tumorigenesis and model the tumor types developed in Tax transgenic mice. Tax exerts its oncogenic role predominantly by activating the cellular transcription factor NF-κB. Here, we report that genetic deletion of NF-κB1, the prototypic member of the NF-κB family, promotes adrenal medullary tumors but suppresses neurofibromas in mice with transgenic Tax driven by the HTLV-I Long Terminal Repeat (LTR) promoter. The adrenal tumors are derived from macrophages. Neoplastic macrophages also infiltrate the spleen and lymph nodes, causing splenomegaly and lymphadenopathy in mice. Nevertheless, the findings could be human relevant, because macrophages are important target cells of HTLV-I infection and serve as a virus reservoir in vivo. Moreover, the spleen, lymph nodes and adrenal glands are the most common sites of tumor cell infiltration in HTLV-I-infected patients. These data provide new mechanistic insights into the complex interaction between Tax and NF-κB, therefore improving our understanding of HTLV-I oncogenic pathogenesis. They also expand our knowledge and establish a new animal model of macrophage neoplasms and adrenal tumors.

Period prevalence of uveitis in human T-lymphotropic virus 1 carriers versus noncarriers in a highly endemic area: The Nagasaki Islands Study.

The magnitude of the effect of human T-lymphotropic virus 1 (HTLV-1) infection on uveitis remains unclear. We conducted a cross-sectional study in a highly endemic area of HTLV-1 in Japan. The study included 4265 residents (men, 39.2%), mostly middle-aged and older individuals with a mean age of 69.9 years, who participated in our surveys between April 2016 and September 2022. We identified HTLV-1 carriers by screening using chemiluminescent enzyme immunoassays and confirmatory tests, and the proportion of carriers was 16.1%. Participants with uveitis were determined from the medical records of all hospitals and clinics where certified ophthalmologists practiced. We conducted logistic regression analyses in an age- and sex-adjusted model to compute the odds ratio (OR) and 95% confidence interval (CI) of uveitis according to HTLV-1 infection status. Thirty-two (0.8%) participants had uveitis. For HTLV-1 carriers, the age- and sex-adjusted OR (95% CI) of uveitis was 3.27 (1.57-6.72) compared with noncarriers. In conclusion, HTLV-1 infection was associated with a higher risk of uveitis among mostly middle-aged and older Japanese residents in a highly endemic HTLV-1 area. Our findings suggest that physicians who treat HTLV-1 carriers should assess ocular symptoms, and those who diagnose patients with uveitis should consider HTLV-1 infection.

Diagnóstico de la infección por el virus linfotrópico de los linfocitos T humano y estrategias para ampliar el tamizaje conexo en el contexto de la salud maternoinfantil. Informe de la reunión (virtual) celebrada el 7 de julio del 2023

En los últimos años, la OPS ha estado colaborando con diferentes interesados directos —como especialistas en VLTH‑1, gerentes de programas de salud y personas con infección por el VLTH‑1— a fin de definir prioridades y delinear estrategias eficaces para hacer frente a esta infección desatendida. Una de las prioridades definidas por los interesados directos es la prevención de la transmisión maternoinfantil del VLTH‑1. Sin embargo, para que sea posible prevenir la transmisión vertical, las embarazadas con infección por el VLTH‑1 deben conocer su estado serológico respecto a esta infección. En la Región de las Américas, la cobertura del tamizaje del VLTH‑1 en donantes de sangre es alta, aunque el tamizaje prenatal sigue siendo limitado. Los países siguen encontrando obstáculos para implantar el uso de las pruebas de diagnóstico de la infección por el VLTH. No hay directrices internacionales para el diagnóstico de la infección por el VLTH‑1 y la orientación nacional puede variar de un país a otro. En este contexto, la OPS organizó un taller para debatir sobre el diagnóstico de la infección por el VLTH‑1, en particular en el contexto de la salud maternoinfantil. En la Región de las Américas se observa un interés cada vez mayor por el tamizaje prenatal de la infección por el VLTH‑1 y algunos países como Chile, Brasil, Santa Lucía y Colombia transmitieron su experiencia durante el taller. Entre las buenas prácticas figuran el programa para prevenir la transmisión maternoinfantil del VLTH‑1, integrado en la iniciativa ETMI Plus, en Santa Lucía; la estrecha colaboración entre la sociedad civil, expertos en la infección por el VLTH‑1 y responsables de las políticas en Brasil; iniciativas para aumentar la concientización sobre la infección por el VLTH‑1 en la Región; y la elaboración de directrices clínicas sobre la infección por el VLTH por distintos países de la Región. Se determinaron diversas prioridades, como aumentar la concientización acerca de la infección por el VLTH, elaborar directrices y capacitación de apoyo para los profesionales de la salud, fortalecer la colaboración entre países y promover la inclusión de la infección por el VLTH en los programas de eliminación.

The diagnosis of human T lymphotropic virus (HTLV) and strategies to expand HTLV screening in the context of maternal and child health. Meeting Report (virtual), 7 July 2023

In recent years, PAHO has been engaging with different stakeholders, including HTLV‑1 specialists, health managers and people living with HTLV-1 to define priorities and to delineate effective strategies to tackle this neglected infection. One of the priorities identified by stakeholders is the prevention of HTLV-1 mother-to-child transmission. However, to be able to prevent vertical transmission, pregnant women living with HTLV-1 must be aware of their status. The coverage of HTLV-1 screening of blood donors is high in the region, but antenatal screening is still limited. Countries still face barriers to implement diagnostic tests for HTLV. There are no international guidelines for HTLV-1 diagnostics and national guidance may vary between countries. In this context, PAHO promoted a workshop to discuss the diagnosis of HTLV-1 infection, particularly in the context of maternal and child health. Increased interest on HTLV-1 antenatal screening has been observed in the region and countries such as Chile, Brazil, Saint Lucia and Colombia shared their experience during the workshop. Good practices included the program to prevent HTLV-1 mother-to-child transmission, that is integrated with the EMTCT Plus initiative in Saint Lucia, strong collaboration between civil society, HTLV-1 experts and policy-makers in Brazil, initiatives to increase awareness about HTLV-1, and the construction of HTLV clinical guidelines by different countries in the Region. Priorities identified include increasing awareness about HTLV, developing guidelines and support training of health-care workers, strengthening the collaboration between countries, and promoting the inclusion of HTLV into elimination programs.

Diagnóstico de infecção por vírus linfotrópico de células T humanas e estratégias para expandir a triagem relacionada no contexto da saúde materno-infantil Relatório da reunião (virtual) realizada em 7 de julho de 2023

Nos últimos anos, a OPAS vem colaborando com diferentes partes interessadas, como especialistas em HTLV‑1, administradores de saúde e pessoas vivendo com HTLV‑1, a fim de definir prioridades e delinear estratégias efetivas para combater essa infecção negligenciada. Uma das prioridades identificadas pelas partes interessadas é a prevenção da transmissão materno-infantil do HTLV‑1. No entanto, para poder prevenir a transmissão materno-infantil, as gestantes vivendo com HTLV‑1 precisam estar cientes do próprio estado sorológico. A cobertura da triagem de HTLV‑1 em doadores de sangue é alta na Região das Américas, mas a triagem pré-natal continua limitada. Os países continuam enfrentando barreiras para implementar testes diagnósticos de HTLV. Não há diretrizes internacionais para o diagnóstico do HTLV‑1, e as orientações nacionais podem variar entre países. Nesse contexto, a OPAS organizou uma oficina para discutir o diagnóstico da infecção pelo HTLV‑1, particularmente no contexto da saúde materno-infantil. Tem-se observado maior interesse na triagem pré-natal do HTLV‑1 na Região, e países como Chile, Brasil, Santa Lúcia e Colômbia compartilharam suas experiências durante a oficina. Exemplos de boas práticas incluíram um programa para prevenir a transmissão materno-infantil do HTLV‑1 que está integrado à iniciativa EMTCT Plus em Santa Lúcia; uma forte colaboração entre sociedade civil, especialistas em HTLV‑1 e formuladores de políticas no Brasil; iniciativas para aumentar a conscientização sobre o HTLV‑1 na Região; e a elaboração de protocolos clínicos para o HTLV em diferentes países da Região. As prioridades identificadas incluem aumentar a conscientização sobre o HTLV, desenvolver diretrizes e apoiar a capacitação de profissionais de saúde, fortalecer a colaboração entre os países e promover a inclusão do HTLV nos programas de eliminação.

Inflammatory progressive multifocal leukoencephalopathy with human T-cell lymphotropic virus-1 coinfection.

A middle-aged man with progressive multifocal leukoencephalopathy (PML) in a human T-cell lymphotropic virus type-1 (HTLV-1) carrier on haemodialysis presented with mild dysarthria and ataxia. Brain MRI revealed asymmetric T2-hyperintense lesions in the cerebral white matter, cerebellum and brainstem. A small amount of JC virus (JCV) genome in cerebrospinal fluid was detected by PCR and cerebellar biopsy demonstrated JCV-DNA presence. Pathological findings showed demyelinating lesions and glial cells with mildly enlarged nuclei, accompanied by T-lymphocytes, neutrophils and plasma cell infiltration. The CD4+/CD8+ratio was 0.83. High-dose corticosteroid therapy was effective for inflammatory PML lesions, and the administration of mefloquine combined with mirtazapine led to favourable outcome. The encephalitis in this case is considered to have occurred secondarily to JCV infection in the presence of HTLV-1 infection. Therefore, it is crucial to investigate the presence of HTLV-1 in order to understand the aetiology of this brain inflammation.

Non-cancerous complications in HTLV-1 carriers.

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

Evaluating a Retro-Inverso Type Inhibitor of HTLV-1 Protease as a Competitive Inhibitor.

The inhibition mode of a retro-inverso (RI) inhibitor containing a hydroxyethylamine dipeptide isostere against the human T-cell leukemia virus type-1 (HTLV-1) protease was examined. Enzymatic evaluation of the RI-modified inhibitor containing a D-allo-Ile residue revealed that HTLV-1 was competitively inhibited. IC50 values of the RI-modified inhibitor and pepstatin A, a standard inhibitor of aspartic proteases, were nearly equivalent.

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.

HTLV in Sweden.

Sweden is a country with a low prevalence of human lymphotropic T-cell virus (HTLV) infection, estimated at < 0.005%, but the infection rate is notably higher in specific risk groups such as HTLV-2 among intravenous drug users (IVDU) and people originating from HTLV-1 highly endemic areas. Thus, in the most recent study from 2012, the prevalence of HTLV-2 among IVDU in Stockholm was 3.2%. However, much of the epidemiological data on HTLV in Sweden stems from studies conducted primarily between the 1990s and 2007, and the impact of migration to Sweden during the past 15 years has not been evaluated. Despite Sweden's status as a country with generally low prevalence of HTLV, it is prudent to anticipate and prepare for several potential challenges associated with HTLV infection in the future. Proactive measures to enhance awareness, alongside strategies to curtail transmission and mitigate complications, are crucial for addressing this relatively rare, but significant health issue. In this work, we review the current epidemiological knowledge about HTLV in Sweden and discuss future Swedish perspectives.

Prevalence of HTLV-1/2 infection in pregnant women in Central and South America and the Caribbean: a systematic review and meta-analysis.

BACKGROUND: Human T-lymphotropic viruses (HTLV)-1 infection is endemic in many countries of Central and South America and Caribbean (CSA&C). Neither screening nor surveillance programs exist for HTLV-1/2 infection among pregnant women in this region. Neither in Western nations with large migrant flows from HTLV-1/2 endemic regions. METHODS: Systematic review and meta-analysis of the prevalence of HTLV-1/2 infection among CSA&C pregnant women. We included studies searching EMBASE, PubMed/MEDLINE, Scopus, and Web of Science from inception to February 15, 2023. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. RESULTS: We identified a total of 620 studies. Only 41 were finally included in the meta-analysis. Most studies (61.0%) were from Brazil and Peru (14.6%). The total number of participants was 343,707. The pooled prevalence of HTLV-1/2 infection among CSA&C pregnant women was 1.30% (95% CI: 0.96-1.69) using anti-HTLV-1/2 antibody screening tests. There was a high heterogeneity (I2 = 98.6%). Confirmatory tests gave an HTLV-1 infection rate of 1.02% (95% CI: 0.75-1.33). CONCLUSIONS: The prevalence of HTLV-1/2 infection among CSA&C pregnant women is 1.3%, most cases being HTLV-1. This rate is greater than for other microbial agents regularly checked as part of antenatal screening (such as HIV, hepatitis B, or syphilis). Thus, HTLV-1/2 antenatal testing should be mandatory among CSA&C pregnant women everywhere.

Case Report: Disseminated Paracoccidioidomycosis and Strongyloides Hyperinfection in a Patient with Human T-Lymphotropic Virus Type 1/2 Infection.

Co-occurrence of paracoccidioidomycosis and strongyloidiasis in immunosuppressed patients, particularly those infected with human T-lymphotropic virus type 1/2, is infrequent. We describe the case of a Peruvian farmer from the central jungle with human T-lymphotropic virus type 1/2 infection, with 2 months of illness characterized by respiratory and gastrointestinal symptoms associated with fever, weight loss, and enlarged lymph nodes. Strongyloides stercoralis and Paracoccidioides brasiliensis were isolated in sputum and bronchoalveolar lavage samples, respectively. The clinical evolution was favorable after the patient received ivermectin and amphotericin B. We hypothesize that autoinfestation by S. stercoralis in human T-lymphotropic virus type 1/2-infected patients may contribute to the disseminated presentation of Paracoccidioides spp. Understanding epidemiological context is crucial for suspecting opportunistic regional infections, particularly those that may coexist in immunosuppressed patients.

Multicenter, randomized, double-blind, placebo-controlled phase 3 study of mogamulizumab with open-label extension study in a minimum number of patients with human T-cell leukemia virus type-1-associated myelopathy.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin.

A typical HTLV-1-infected individual carries >104 different HTLV-1-infected T cell clones, each with a single-copy provirus integrated in a unique genomic site. We previously showed that the HTLV-1 provirus causes aberrant transcription in the flanking host genome and, by binding the chromatin architectural protein CTCF, forms abnormal chromatin loops with the host genome. However, it remained unknown whether these effects were exerted simply by the presence of the provirus or were induced by its transcription. To answer this question, we sorted HTLV-1-infected T-cell clones into cells positive or negative for proviral plus-strand expression, and then quantified host and provirus transcription using RNA-seq, and chromatin looping using quantitative chromosome conformation capture (q4C), in each cell population. We found that proviral plus-strand transcription induces aberrant transcription and splicing in the flanking genome but suppresses aberrant chromatin loop formation with the nearby host chromatin. Reducing provirus-induced host transcription with an inhibitor of transcriptional elongation allows recovery of chromatin loops in the plus-strand-expressing population. We conclude that aberrant host transcription induced by proviral expression causes temporary, reversible disruption of chromatin looping in the vicinity of the provirus.