How Can We Prevent Mother-to-Child Transmission of HTLV-1?

The perception of human T-cell leukemia virus type 1 (HTlV-1) infection as a "silent disease" has recently given way to concern that its presence may be having a variety of effects. HTLV-1 is known to cause adult T-cell leukemia (ATL), an aggressive cancer of peripheral CD4 T cells; however, it is also responsible for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Most patients develop ATL as a result of HTLV-1 mother-to-child transmission. The primary route of mother-to-child transmission is through the mother's milk. In the absence of effective drug therapy, total artificial nutrition such as exclusive formula feeding is a reliable means of preventing mother-to-child transmission after birth, except for a small percentage of prenatal infections. A recent study found that the rate of mother-to-child transmission with short-term breastfeeding (within 90 days) did not exceed that of total artificial nutrition. Because these preventive measures are in exchange for the benefits of breastfeeding, clinical applications of antiretroviral drugs and immunotherapy with vaccines and neutralizing antibodies are urgently needed.

Rapid onset and progression of myelopathy following an STI: a case for screening?

Human T lymphotropic virus type 1 (HTLV-1) is recognised as an STI with serious manifestations of the disease in approximately 10% of those infected. This case report is the first to describe the short interval from sexual acquisition of HTLV-1 to the onset of HTLV-1-associated myelopathy and rapid progression to spastic paraparesis. The number of adult infections in the UK per annum is unknown, but surveillance data indicate that around 30% of newly diagnosed infections are occurring in persons born in the UK, rather than in migrants from HTLV-1-endemic regions. Despite this, and despite the risk of chronic debilitating disease, HTLV-1 infection is not part of sexual health screening in the UK, with the consequence that patients requesting sexual health screens are not informed of their carrier status and transmission from asymptomatic carriers to the partners will continue.

Brief Report: Attenuated Effectiveness of Tumor Necrosis Factor Inhibitors for Anti-Human T Lymphotropic Virus Type I Antibody-Positive Rheumatoid Arthritis.

OBJECTIVE: To evaluate the effectiveness of tumor necrosis factor (TNF) inhibitors for the treatment of human T lymphotropic virus type I (HTLV-I)-positive patients with rheumatoid arthritis (RA) in an area endemic for HTLV-I infection. METHODS: We conducted an observational study of 585 RA patients in whom TNF inhibitors were newly introduced as a first biologic disease-modifying antirheumatic drug in an area in southwestern Japan that is endemic for HTLV-I infection. RESULTS: Fifty patients (8.5%) were anti-HTLV-I antibody-positive. The ages of the patients in this group were significantly higher at entry compared with the ages of patients who were anti-HTLV-I antibody-negative (n = 535). The median Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was 5.21. Among the total group of patients, 82% were anti-citrullinated protein antibody (ACPA)-positive. The persistence rate of TNF inhibitors at 24 weeks was 89%. The median DAS28-ESR was significantly decreased at 24 weeks in each group. The European League Against Rheumatism (EULAR) response rate was significantly better in the anti-HTLV-I antibody-negative patients (P = 0.0277). Multiple regression analysis demonstrated that anti-HTLV-I antibody status was significantly associated with the EULAR response rate and change in the DAS28-ESR and was prominent especially in the ACPA-negative subjects. No patients developed adult T cell leukemia/lymphoma (ATL) or HTLV-I-associated myelopathy (HAM) during the 24-week treatment period. CONCLUSION: The efficacy of TNF inhibitors may be attenuated in anti-HTLV-I antibody-positive patients with RA. ATL and HAM did not develop when TNF inhibitors were used for 24 weeks, but the long-term risk is not known.

Vírus Linfotrópico Humano (HTLV)

O vírus linfotrópico de células T humanas tipo 1 (HTLV-1- “Human T lymphotropic vírus type 1”) foi o primeiro retrovírus humano descrito. O vírus foi inicialmente associado com a leucemia de células T do adulto (ATL) no Japão em 1977, sendo depois encontrado em diversas partes do mundo. Posteriormente, foi associado às doenças neurológicas Paraparesia Espástica Tropical (TSP) e Mielopatia Associada ao HTLV (HAM), que hoje é conhecida como HAM/TSP.

Reducing the global burden of HTLV-1 infection: An agenda for research and action.

Even though an estimated 10-20 million people worldwide are infected with the oncogenic retrovirus, human T-lymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new infections. In the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines.

Paraparesia espástica tropical vista desde un contexto ibérico. Réplica / Tropical spastic paraparesis viewed from an Iberian context. Reply

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Human T-lymphotropic virus type 1 prevalence in northeastern Iran, Sabzevar: an epidemiologic-based study and phylogenetic analysis.

Human T-lymphotropic virus type 1 (HTLV-I) is an important global health problem in the world mainly in the endemic areas of HTLV-I infection. It was previously reported that Mashhad, in northeastern Iran, is a new endemic region of HTLV-I. The aim of this study was to examine the prevalence and phylogenetic analysis of HTLV-I in Sabzevar, located in the southeast of Mashhad. In this cross-sectional study 1445 individuals were selected by multistage cluster sampling. Serum samples were screened for anti-HTLV-I antibody using enzyme-linked immunosorbent assay (ELISA); all of the ELISA-positive samples were confirmed by polymerase chain reaction (PCR). Long terminal repeat (LTR) sequencing was carried out to determine the type of HTLV-I in Sabzevar. In the primary screening by ELISA, 26/1445 (1.8%) of those sampled were reactive for HTLV-I antibody. Twenty-four out of 26 samples were confirmed HTLV-I infection by PCR (24/1445). The overall prevalence of HTLV-I infection in Sabzevar is 1.66%. The prevalence of the virus infection in men and women was 2.42% (11/455) and 1.31% (13/989), respectively. Seroprevalence was associated with age, increasing significantly among those older than 30 years (p=0.015), and a history of surgery (p=0.002), imprisonment (p=0.018), and hospitalization (p=0.005). Three out of 24 positive HTLV-I samples were selected for sequencing and phylogenetic analysis of LTR. The results showed that HTLV-I in Sabzevar belonged to the cosmopolitan subtype. The present study showed Sabzevar is a new endemic area for HTLV-I infection. Our study emphasizes that systemic HTLV-I screening of blood donors in Sabzevar and other cities in Khorasan province is important and should be taken into account.

Fucoidan therapy decreases the proviral load in patients with human T-lymphotropic virus type-1-associated neurological disease.

BACKGROUND: Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus that causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia (ATL). A higher viral load in individuals with HTLV-1 infection increases their risk of developing HAM/TSP and ATL. Moreover, the high proviral load is associated with the clinical progression of HAM/TSP. Reduction of the number of HTLV-1-infected cells is therefore crucial for preventing and treating HTLV-1-associated diseases. Recently, fucoidan, a complex sulphated polysaccharide derived from marine seaweed, has been demonstrated to exert inhibitory effects on HTLV-1 infection in vitro. In this study, we examined the in vivo effects of fucoidan on HTLV-1 infection. METHODS: In this single-centre open-label trial, 13 patients with HAM/TSP were treated with 6 g fucoidan daily for 6-13 months. The HTLV-1 proviral DNA load and frequencies of HTLV-1-specific CD8(+) T-cells, natural killer cells, invariant natural killer T-cells and dendritic cells in the peripheral blood were analysed. Furthermore, the in vitro inhibitory effect of fucoidan on cell-to-cell HTLV-1 infection was examined by using luciferase reporter cell assays. RESULTS: Fucoidan inhibited the cell-to-cell transmission of HTLV-1 in vitro. Furthermore, fucoidan therapy resulted in a 42.4% decrease in the HTLV-1 proviral load without affecting the host immune cells. During the treatment, no exacerbation was observed. Four patients with HAM/TSP developed diarrhoea, which improved immediately after stopping fucoidan administration. CONCLUSIONS: Fucoidan is a new potential therapeutic agent for the prevention and treatment of HTLV-1-associated diseases.

HTLV-1 provirus load in peripheral blood lymphocytes of HTLV-1 carriers is diminished by green tea drinking.

Human T-cell lymphotropic virus type 1 (HTLV-1) is causatively associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since a high level of HTLV-1 provirus load in circulating lymphocytes is thought to be a risk for ATL and HAM/TSP, diminution of HTLV-1 provirus load in the circulation may prevent these intractable diseases. Our previous study (Jpn J Cancer Res 2000; 91: 34-40) demonstrated that green tea polyphenols inhibit in vitro growth of ATL cells, as well as HTLV-1-infected T-cells. The present study aimed to investigate the in vivo effect of green tea polyphenols on HTLV-1 provirus load in peripheral blood lymphocytes on HTLV-1 carriers. We recruited 83 asymptomatic HTLV-1 carriers to examine HTLV-1 provirus DNA with or without administration of capsulated green tea extract powder. Thirty-seven subjects were followed up for 5 months by measuring HTLV-1 provirus load after daily intake of 9 capsules of green tea extract powder per day (equivalent to 10 cups of regular green tea), and 46 subjects lived ad libitum without intake of any green tea capsule. The real-time PCR quantification of HTLV-1 DNA revealed a wide range of variation of HTLV-1 provirus load among asymptomatic HTLV-1 carriers (0.2-200.2 copies of HTLV-1 provirus load per 1000 peripheral blood lymphocytes). Daily intake of the capsulated green tea for 5 months significantly diminished the HTLV-1 provirus load as compared with the controls (P = 0.031). These results suggest that green tea drinking suppresses proliferation of HTLV-1-infected lymphocytes in vivo.

Pathogenesis and prevention of HTLV-1-associated diseases.

HTLV-1 is an important factor involved in various diseases including adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis. Amount of HTLV-1 provirus integrated in human peripheral blood mononuclear cells might be a candidate for a risk factor in the manifestation of HTLV-1 associated diseases. Experimental animal models would be useful to dissect the pathogenesis of HTLV-1 associated diseases. We present rat and mouse models of HTLV-1 infection. Using these animal models, we could clarify the intrauterine transmission of HTLV-1, and have found that both genetic background and HTLV-1 infection are important in pathogenesis of HAM/TSP-like rats. We also discuss the preventive measures of HTLV-1 transmission by use of antisense oligonucleotides.

An HTLV-I/II vaccine: from animal models to clinical trials?

A human T-lymphotropic virus type I/II (HTLV-I/II) vaccine is necessary in view of two etiologically related, life-threatening diseases, namely, adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. When the risk of developing autoimmune diseases such as uveitis, polymyositis, and arthritis is included, one can estimate the life-long risk of infected individuals to develop an HTLV associated pathology as approximately 10%. The populations at risk are, in a large majority, from developing countries but the epidemic of HTLV-II infection in intravenous drug users (IVDU) represents a possible reservoir for dissemination in the general population. The number of HTLV-I-infected individuals (15 to 25 million), together with the severity of associated disease, justifies the development of a vaccine. Different vaccine preparations have been developed, using mostly recombinant pox and adenoviruses, but DNA plasmid technology will soon become a feasible approach. Various animal models exist for experimental viral infections, involving rats, rabbits, or monkeys, but up to now, neither hematological nor neurological disorders have been induced by HTLV infection in such animal models. For long-term protection from HTLV-I-associated diseases, vaccination should induce both neutralizing antibodies and specific cell-mediated immunity. This will require the incorporation of both env and gag coding sequences in the vaccine preparations. Preventive clinical trials may involve different cohorts of seronegative young girls from endemic areas prior to sexual activity and IVDU in the industrialized world. In parallel, one should consider therapeutic vaccine trials in HTLV-I-positive mothers and IVDU to protect them against disease development. The observed rate of seroconversion in these different cohorts makes such trials feasible.

Mielopatía HTLV-I positivo

La mielopatía HTLV-I positivo es una enfermedad de origen viral, caracterizada por comienzo lento, dolor lumbar y trastornos de la marcha; puede presentar diversos grados de compromiso, desde las formas asintomáticas hasta cuadros severos crónicos con postración total al lecho, Después de muchas especulaciones de tipo nutricional, neurotóxico, bacteriano, etc., hoy se conoce que sus agentes causales son retrovirus HTVL-I y HTVL-II. Las manifestaciones clínicas una vez instalado el cuadro patológico son sificultad para la marcha, notable disminución de la líbido, compromiso de esfinteres y una lenta y progresiva incapacidad para sostenerse en pie. La enfermedad afecta por igual a hombres y mujeres, a veces con carácter familiar, y la mayoría de los pacientes están alrededor de 30 - 35 años. La evolución en promedio es de unos 3-5 años, aunque hay pacientes cuya enfermedad tiene 10 a 20 años de duración. Ningún paciente fallece por causa de la enfermedad. Presentamos una relación de los casos observados en el área de influencia de nuestro Hospital Universitario San José

Human T cell lymphotropic virus: necessity for and feasibility of a vaccine.

Human T cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world. They cause two life-threatening diseases, adult T cell leukaemia/lymphoma and tropical spastic paraparesis. A vaccine is needed because in developing countries there are no other feasible preventive interventions against these diseases and in Western countries intravenous drug users at high risk for HTLV-I and HTLV-II infections and the health workers in contact with such populations must be protected. We have developed a rat model in which we observed variations of susceptibility to viral infection between inbred strains, the most susceptible being the Fischer F344, and the possibility of viral latency in the nervous system. We have prepared a recombinant adenovirus vector that expresses the HTLV-I envelope glycoprotein env in HeLa cells. A target human population in French Guyana, in which the prevalence rate reaches 5.6% in one ethnic group (Bonis), has been identified for possible intervention.

Human T cell lymphotropic virus: necessity for and feasibility of a vaccine

Human T cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world. The cause two life-threatening diseases, adult T cell leukaemia/lymphoma and tropical spastic paraparesis. A vaccine is needed because in developing countries there are no other feasible preventive interventions against these diseases and in Western countries intravenous drug users at high risk for HTLV-I and HTLV-II infections and the health workers in contact with such populations must be protected. We have developed a rat model in which we observed variations of susceptibility to viral infection between inbred strains, the most susceptible being Fischer F344, and the possibility of viral latency in the nervous system. We have prepared a recombinant adenovirus vector that expresses the HTLV-I envelope glycoprotein env in HeLa cells. A target human population in French Guyana, in which the prevalence rate reaches 5.6 percent in one ethnic group (Bonis), has been identified for possible intervention (AU)

Human T-cell lymphotropic virus type I and II in transfusion medicine.

As a consequence of migrating populations, IV drug use and, to a lesser extent, blood transfusions, endemic HTLV-I and HTLV-II infections have spread to nonendemic geographic regions. Although the risk that a person infected with HTLV-I will develop significant disease--even over a lifetime--is estimated to be relatively low, our awareness of the serious diseases associated with other retroviruses requires a cautious approach to blood transfusion. Reports from Japan and the United States indicate that programs testing donated blood and excluding units with HTLV-I antibodies have been highly successful in interrupting the spread of HTLV-I by transfusions. One unanticipated outcome of testing large numbers of people in the United States for HTLV-I antibodies has been recognition of the relatively high prevalence of HTLV-II infection, particularly among IV drug users. The long-term effects of HTLV-II infection are also unknown. Until the natural history and clinical consequences of HTLV-II infection are clearly understood, it is only prudent that blood donated by persons identified to be HTLV-II carriers also be excluded.