Tools
Human T-Cell Lymphotropic Virus
Introduction
Human T-lymphotropic viruses (HTLVs) are a family of human retroviruses recognized as oncoviruses. These viruses are known for causing immunosuppressive and inflammatory diseases. Among them, HTLV-1 is the most clinically significant and was the first pathogen demonstrated to induce malignant disease. HTLV-1 was identified in 1980 from a cell line derived from a patient with cutaneous T-cell lymphoma.[1]
The discovery of HTLV-1 marked the first identification of a human retrovirus, sparking further investigations into the relationship between hematological malignancy and retroviruses. Today, HTLV-1 is regarded as one of the most potent oncogenic agents in humans.[2] Although approximately 95% of infected individuals remain asymptomatic, about 5% may develop malignant, inflammatory, or opportunistic disease. Clinical manifestations include HTLV-1–associated myelopathy (HAM) and tropical spastic paraparesis (TSP).
HTLV-2, identified from hairy T-cell leukemia cell lines in 1982, is associated with a phenotype presentation similar to HAM/TSP in a small percentage of affected individuals.[3][4] Unlike HTLV-1, however, HTLV-2 has not been clearly associated with malignancy. Similarly, HTLV-3 and HTLV-4 have not been shown to have causative relationships with malignancy.[5]
HTLV-1 exhibits a strong oncogenic potential and carries a higher incidence of associated complications compared to other members of the HTLV family. The etiology, pathophysiology, evaluation, and management of HTLV-1 are fundamental to understanding its clinical significance.
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
HTLV-1 is an enveloped, single-stranded RNA retrovirus. The genomic organization of HTLV-1 is characteristic of the Retroviridae family, comprising 2 long terminal repeat (LTR) sequences, along with the group-specific core antigen (Gag), polymerase (Pol), and envelope (Env) genes. A distinguishing feature of HTLV-1 is the additional identifying pX region, which encodes several regulatory proteins, including the Tax protein. The Tax protein is strongly implicated in the pathophysiology of HTLV-1.[6]
HTLV-1 infection occurs primarily and most efficiently via the transmission of infected lymphocytes, although free viral particles have been demonstrated to infect dendritic cells.[7] Once infected, CD4+ cells produce CCL22 (a CCR4 ligand), which attracts CCR4-expressing CD4+ cells to form what is termed the virological synapse.[8] This process potentiates preferential transmission of HTLV-1 within a CCR4+ CD4+ T-cell population.
Although both HTLV-1 and HIV infect T cells, there are essential differences in their virology and pathophysiology.[9] This mode of cell-to-cell transmission is an example of one such difference and results in the very low viremia observed in HTLV-1 infection, in contrast to the high viral loads of HIV.
After infection of T-cell lines, HTLV-1 replication is thought to occur mainly through clonal expansion, reducing the need for high replication rates.[10] This characteristic contributes to the virus's long latency, allowing it to remain dormant in lymphocytes for years before, in some cases, leading to oncogenic transformation and the development of HAM/TSP or adult T-cell leukemia.
A second defining feature of HTLV-1 is its genetic stability, which is maintained by its replication strategy.[11] Following reverse transcription and integration into the host genome, replication occurs either through re-expression of the provirus or via host cell mitosis, whereby the provirus is duplicated with the genome. Because replication depends on host cell division rather than an independent viral polymerase, viral turnover is low while transcription fidelity remains high.[12] This produces a genetically stable product, sharply contrasting with the variability of HIV and conferring resistance to immune escape.[13]
HTLV-1 can regulate its own transcription and, therefore, transiently expresses gene products that contribute to evading host immune control.[14] Two regulatory proteins facilitate this process—Tax, which activates transcription, and Rex, which suppresses it.[15]
The integration of the provirus and subsequent translation of viral products promote cellular proliferation and enhanced survival, thereby ensuring viral persistence. Unlike HIV infection, HTLV-1 does not induce cellular death; instead, T cells evade apoptosis and are prone to transformation.[16]
HTLV-1 is structurally similar to simian T-lymphocytic virus. Both viruses share a common ancestor, with HTLV-1 emerging in humans through zoonotic exposure.[17][18] Documented cases have shown that HTLV-1 strains closely related to simian T-lymphocytic virus can be transmitted from nonhuman primates to human hunters.[19]
HTLV-1 consists of multiple molecular subtypes, classified from A to G based on the coding and noncoding regions of the proviral genomes.[20] These subtypes are thought to have evolved from ancestral simian strains that coevolved with humans over thousands of years.
This distribution of subtypes is geographically distinct. HTLV-1a is the most widespread, particularly across Africa and Japan, whereas HTLV-1c is found predominantly among Australo-Melanesian populations and may have originated from Southeast Asia.[21][22]
Ongoing research is exploring the relationship between viral subtype and disease predisposition. For example, evidence suggests that subtype 1c may be more strongly associated with bronchial disease.[23]
Epidemiology
HTLV-1 is estimated to infect 10 to 20 million people worldwide.[24] HTLV-1 is endemic in Japan, parts of Africa, central Australia, South America, and the Caribbean, though the actual number is difficult to estimate due to limited systematic serological testing. Although global endemics of HTLV-1 and HTLV-2 have long been recognized, an emerging epidemic has been noted among intravenous drug users across the United States.[25]
Japan is traditionally recognized as the most endemic country for HTLV-1. Incidence rates have been documented at 3.8 per 100,000 person-years, with higher rates observed in women (6.9 per 100,000 person-years) compared to men (2.3 per 100,000 person-years).[24] In contrast, undercounting in central Australia has masked the true burden of disease. Serosurveys in geographically isolated indigenous communities have revealed prevalence rates as high as 50%.[26][27]
Epidemiological patterns also show sex-based differences in disease expression. Men are more susceptible to adult T-cell leukemia/lymphoma (ATLL), whereas women are more frequently affected by HAM/TSP.[28]
There are 3 major routes of HTLV-1 transmission—vertical transmission from mother to child via breastmilk (the most common route), sexual intercourse, and blood transfusions.[29] HTLV-1 has been isolated in breastmilk, and breastfed children are 4 times more likely to be infected than bottle-fed infants of infected mothers.[30]
Breastfeeding duration is a major factor influencing the risk of transmission. Maternal antibodies transferred during pregnancy appear to provide partial protection for several months after birth. However, after 3 months of breastfeeding, the risk of transmission increases up to 3-fold despite the continued presence of maternal antibodies.[31][32] Short-term breastfeeding is associated with a lower risk, but practical factors, such as maternal-child bonding, limited access to formula, lack of storage facilities, and financial constraints, may prolong weaning, particularly in low-resource and remote communities.
Bottle-fed infants remain at a significantly lower risk, though not entirely free from danger. The estimated risk of transmission rate is 0.6% at 1 year and 4.6% at 4 years.[33]
Sexual transmission accounts for a significant proportion of the HTLV-1 burden in Central Australia. Prevalence is lower among children than in older age groups, suggesting that sexual exposure substantially increases the risk of acquisition from adolescence through adulthood.[27]
Transmission is typically more efficient from males to females, with an estimated rate of 5:1. This imbalance is reflected in global data, where seroconversion rates are consistently higher among females than males.[34][35] However, studies in Australia show a disordant pattern, with higher prevalence reported among men than women, an observation that remains unexplained.[27]
HAM/TSP is associated with sexual transmission and blood transfusion.[36] Vertical and sexual transmission are the most common routes of infection.[37] Risk factors for HAM/TSP include young age at first sexual encounter and having more than 5 lifetime sexual partners.[38] These risk factors are not identified in ATLL, which is more strongly associated with vertical transmission of HTLV-1.
Transfusion of infected blood carries a high risk of rapid seroconversion.[39] This risk has been significantly reduced in countries that routinely screen blood products, such as the United States, Canada, the United Kingdom, Australia, New Zealand, Japan, and Brazil. In the United States, organ donations are also screened for both HTLV-1 and HTLV-2.
Although data on transfusion-related transmission remain limited, small studies suggest that the risk of infection is substantial when a seronegative recipient receives blood from a seropositive donor. In a study involving 10 patients, 7 seroconverted within 4.5 years, and 4 subsequently developed HAM/TSP.[40]
The risk of occupational HTLV-1 exposure among healthcare workers from needlestick injuries has not been clearly quantified but is generally considered low. To date, no postexposure prophylaxis has been established or validated for HTLV-1.
Pathophysiology
HTLV-1 is commonly associated with 2 distinct diseases—ATLL, occurring in approximately 4% of infected individuals, and HAM/TSP, affecting approximately 2%.[28] A well-recognized gender difference exists, with men more susceptible to ATLL, whereas women are more frequently affected by HAM/TSP.[41]
These conditions are associated with various transmission routes. ATLL is primarily related to vertical transmission, whereas HAM/TSP is more closely linked to blood transfusion. Because these transmission routes typically occur at different ages, the age of acquisition likely plays a crucial role in determining disease outcome. No significant differences in HTLV-1 strains have been identified, suggesting that a combination of cofactors and host immune responses determines clinical manifestations.
Viral gene products interact with host transcription factors to mediate cellular transformation and, therefore, oncogenesis. Among these, Tax is the principal viral protein responsible for disruption via several routes.
Tax upregulates T-cell survival pathways through interleukin (IL)-2 (IL-2) and IL-15 signaling and inhibits apoptosis by stimulating Bcl-XL, which prevents caspase activation. At the same time, Tax suppresses cell cycle control and DNA repair. Intracellularly, NF-κB activation drives inflammation, whereas HTLV-1 has also been shown to induce class-switching of T cells toward a T-helper 1 cell profile, further enhancing proinflammatory responses.[42]
Additional mechanisms include high circulating levels of vascular endothelial growth factor, which promotes angiogenesis.[43] Both HTLV-1 and HTLV-2 have demonstrated the ability to transform human lymphocytes into self-sustaining populations in vitro.
HTLV-1 infection elicits a humoral immune response, characterized by antibodies directed against the viral Gag, Env, and Tax proteins. The cellular response is mediated primarily by HTLV-specific cytotoxic lymphocytes, which recognize epitopes derived from the Tax protein. These cytotoxic cells are present in high numbers among asymptomatic carriers, suggesting a key role in controlling HTLV-1 replication and disease progression.[44]
The interaction between the host immune response and HTLV-1–encoded genes has been shown to facilitate an immunosuppressive environment. During acute infection, an IL-10-dominant cytokine profile emerges, supporting T-cell activity. Persistent viral proliferation contributes to CD8 T-cell exhaustion, leading to impaired virus-specific suppression—an important mechanism underlying both chronic viral-mediated immunosuppression and oncogenesis.[45]
In addition, inflammatory cascades triggered by CD4 T-cell activation are thought to play a central role in the pathogenesis of HAM/TSP.[46] This chronic immune activation contributes to progressive spinal cord inflammation and demyelination, ultimately leading to the characteristic motor deficits of the disease.
History and Physical
Acute HTLV-1 infections are rarely identified or diagnosed because the initial infection is often asymptomatic.[47] Suspected or confirmed cases may prompt an investigation into potential transmission routes, such as a recent blood transfusion or breastfeeding from a mother in an endemic area.
No specific treatment is indicated for acute HTLV-1 infection. However, lifestyle counseling is essential, including guidance on breastfeeding practices, safe sexual activity, and vigilance for evolving clinical symptoms.
ATLL is defined as a neoplastic clonal expansion of CD4+ T cells infected with HTLV-1. The lifetime risk of developing ATLL among individuals infected with HTLV-1 is estimated to be 4% to 7%, with malignant transformation typically occurring after a latency period of up to 30 years.[48][49]
The presenting features of ATLL often include generalized lymphadenopathy, cutaneous lymphadenopathy, cutaneous lesions, hepatosplenomegaly, and immunosuppression, which may be evidenced by the development of opportunistic infections. Paraneoplastic hypercalcemia is typically present at diagnosis and may be caused by tumor necrosis factor-β or parathyroid hormone-related protein. Accelerated bone turnover and lytic bone lesions are also frequent findings.[50] Patients in the early stages of disease may lack typical manifestations, and in some cases, presentation is delayed until the onset of fulminant disease.[51]
Classifications of ATLL
The wide variability in clinical presentation and disease course of ATLL has led to its subclassification into 4 categories—acute, characterized by aggressive disease with leukemic features; lymphomatous, marked by predominant nodal involvement without circulating malignant cells; chronic, associated with leukemic features but a more indolent course; and smoldering, defined by minimal symptoms and slow progression.[52] This classification provides important prognostic value and guides therapeutic decision-making.
- Acute: The acute type is the most common presentation of ATLL, accounting for approximately 55% of cases, and is associated with the poorest prognosis, with a median survival of only 6 months from diagnosis. Clinical features include skin lesions, bone pain caused by hypercalcemia, and lytic bone lesions, as well as pulmonary symptoms with infiltrates visible on chest imaging. Pulmonary features may result from primary disease or from opportunistic infections, which are present in 30% of patients at the time of diagnosis. Opportunistic organisms include Pneumocystis jirovecii (causing pneumonia, often observed in patients with AIDS), Cryptococcus neoformans (leading to occult meningitis),[53] Herpes zoster, and Strongyloides stercoralis infestation, which can cause life-threatening hyperinfection.[46][54]
- Lymphomatous: The lymphomatous form accounts for 20% of ATLL cases. This form is characterized by massive lymphadenopathy and splenomegaly, typically without tumor cells.[55] Skin lesions may also occur, and hypercalcemia is common at presentation, often leading to complications, such as renal impairment and neuropsychiatric disturbance.
- Chronic: The chronic subtype accounts for approximately 20% of all ATLL cases and has a more indolent course than the acute and lymphomatous forms. Median survival is around 2 years.[52]
- Smoldering: The smoldering subtype is the rarest form of ATLL, accounting for only 5% of the disease burden. Cutaneous features are common but generally milder than those observed in the acute subtype. Respiratory or gastrointestinal symptoms are typically absent. Diagnostic criteria include involvement of fewer than 5% of peripheral CD4+ T cells.[56] Median survival without treatment is 3 years.
HAM/TSP
HTLV-1–associated myelopathy/TSP is a chronic myelopathy that develops and progresses gradually over time. In some cases, however, more rapid deterioration has been observed, which is thought to correlate with high viral loads, although no definitive threshold for increased risk has been established.[57] HAM/TSP occurs in approximately 0.25% to 3% of individuals living with HTLV-1.[49]
The typical presentation of HAM/TSP is a slowly progressive paraparesis with associated spasticity. The earliest physical signs typically appear in the lower limbs, but involvement of the upper limbs may follow. Weakness tends to be more pronounced in the proximal areas.[58] Widespread pyramidal signs are almost always observed.
Sensory signs are typically subtle, with impaired vibration sense indicating the earliest defect; however, a clear sensory level is uncommon. The thoracic spinal cord is the site most commonly affected by viral-mediated inflammation. Many patients also experience severe thoracolumbar back pain, which is among the most debilitating features of the disease and is often difficult to control. Neuropathic agents, in combination with standard analgesics, are typically required for management.[59]
Autonomic dysfunction is a well-recognized feature of HAM/TSP. Patients may experience orthostatic hypotension and disturbances of sweating, including hyperhidrosis or hypohidrosis, which can significantly impair quality of life.[60] Bladder dysfunction is often an early sign, initially presenting as urgency and later progressing to urinary incontinence. Cognitive function is classically intact.
The clinical course of HAM/TSP is highly variable. Some patients experience rapid progression, becoming a wheelchair user within a short period, whereas others maintain minimal weakness even decades after diagnosis. At present, there are no reliable methods to predict disease progression.[61]
Additional Disease Associations
Beyond ATLL and HAM/TSP, HTLV-1 has been implicated in a broad spectrum of additional disease associations across multiple organ systems. Reported conditions include neurological syndromes, dermatologic and ophthalmologic disorders, and rheumatologic and pulmonary manifestations, reflecting the virus's broad pathogenic potential.
Neurologic manifestations: HTLV-1 is linked to a range of other neurological diseases, including subacute meningitis, encephalitis, amyotrophic lateral sclerosis syndromes, and conus medullaris syndrome.[58] These associations are less well established than the 2 primary HLTV-1-related diseases, and the underlying mechanisms remain incompletely understood.
Dermatologic manifestations: HTLV-1 is associated with infective dermatitis, typically affecting the face, scalp, and flexures of infected children. Clinically, it is characterized by an eczematous rash that is frequently secondarily infected with organisms such as Staphylococci and Streptococci species.[62] The condition typically improves during adolescence and is rare in adults. HTLV-1 has been linked to seborrheic dermatitis and dermatophytosis.[46]
Ophthalmologic manifestations: HTLV-1–associated uveitis presents with floaters and blurred vision, frequently affecting both eyes, and is more common in patients younger than 50. On examination, the anterior chamber appears cloudy with cells, and retinal involvement may also be observed, including hemorrhages and exudates. Although patients respond well to topical steroid therapy, relapses are common once treatment is tapered, necessitating long-term management and increasing the risk of steroid-induced glaucoma.[63]
Rheumatologic manifestations: A variety of autoimmune conditions are observed with increased frequency in HTLV-1–infected patients, including polymyositis, fibromyalgia, Sjögren syndrome, and Raynaud disease.[49][46] These associations are believed to result from chronic immune activation and dysregulation driven by persistent viral infection. The overlap between HTLV-1–related immune phenomena and classic autoimmune disease highlights the complex interplay between viral persistence, host response, and systemic inflammation.
Pulmonary manifestations: Bronchiolar disease occurs with a significantly higher incidence in individuals with HTLV-1 compared to the general population. An extensive prospective study in Australia found that 60% of patients hospitalized with bronchiectasis were HTLV-1–positive, compared to a background prevalence of 10%.[64] Similarly, a study in the United Kingdom found that 3% of patients infected with HTLV-1 had computed tomography evidence of bronchiectasis, in contrast to a prevalence of 0.1% in the general population. The underlying mechanism for this association remains unclear.[65]
Furthermore, HTLV-1 infection has been linked to asthma and an increased risk of respiratory infections, including community-acquired pneumonia and tuberculosis. However, much of the supporting evidence comes from small or low-quality observational studies, and these associations remain less defined.[46]
Malignancy manifestations: Malignancies have also been linked to HTLV-1 infection. A meta-analysis demonstrated positive associations with liver cancer, lymphomas other than ATLL, and cervical cancer. Notably, HTLV-1 infection was associated with a lower risk of gastric cancer.[46]
Evaluation
For HTLV-1, the definitive diagnosis relies on serological testing. Enzyme-linked immunosorbent assay is often employed as a screening tool, followed by Western blot as a confirmatory study to identify antibodies against the viral Gag and Env proteins. However, depending on the validity of the Western blot used and laboratory standards, indeterminate results may occur in 5% to 65% of cases.[66] In these cases, molecular testing can be used to confirm HTLV-1 infection.
Polymerase chain reaction (PCR) offers the advantage of quantifying proviral load and differentiating between HTLV-1 and HTLV-2.[67] This method is beneficial for assessing pregnant individuals, as proviral load can help estimate the risk of vertical transmission through breastfeeding. However, PCR requires specialized primers targeting the HTLV Pol gene, and mutations or deletions in this region can complicate standardization and the interpretation of results. As a result, PCR testing is typically conducted in reference laboratories equipped with sufficient reagents and primers to ensure accurate measurement of proviral loads.
The clinical interpretation of proviral load remains uncertain, as no threshold has been identified to reliably predict disease risk or clinical outcomes. The primary value of proviral load lies in assessing the risk of mother-to-child transmission, as higher loads are strongly predictive of vertical transmission.[30] Proviral load does not vary significantly during pregnancy, but it can increase postpartum, particularly when breastfeeding.[68][69] Therefore, accurate testing and comprehensive counseling are essential when treating expectant mothers, especially given the absence of curative HTLV-1.
Further diagnostic tools are under development, including lateral flow assays. Currently, these tests are either awaiting validation or are primarily used for screening purposes rather than diagnosis.[70][71]
In ATLL, patients may present with a markedly elevated white blood cell count and persistent lymphocytosis, depending on the stage of the disease.[72] Diagnostic evaluation requires examination of peripheral blood cells and bone marrow, which also aids in subclassification.
Pathognomonic morphological features of leukemic ATLL lymphocytes include dense chromatin with lobulated, cloverleaf-shaped nuclei, often referred to as flower cells.[73] Scattered blast cells may also be visible on blood film, whereas bone marrow examination typically demonstrates patchy infiltrates.
Histological assessment of lymphoid tissue is essential when lymphomatous disease is suspected. Involved lymph nodes show markedly distorted architecture with pleomorphic cells that can resemble Reed-Sternberg cells, occasionally leading to diagnostic confusion with Hodgkin lymphoma.[72] Similarly, biopsy of cutaneous lesions may reveal findings similar to those of mycosis fungoides, a form of cutaneous T-cell lymphoma.
Several markers have been identified as predictors of disease progression in ATLL, including serum CD25, thymidine kinase, and neuron-specific enolase, though these tests are rarely available outside specialist centers.[74] However, none of these markers have been standardized for routine clinical use, and their utility remains largely confined to research or specialized diagnostic settings.
The World Health Organisation established diagnostic criteria for HAM/TSP in 1988, incorporating clinical, imaging, and laboratory findings. In current practice, however, newer techniques, such as PCR-based quantification of HTLV-1 viral load in cerebrospinal fluid (CSF), are typically incorporated into the diagnostic process.[75] Magnetic resonance neuroimaging may reveal discrete white matter lesions or spinal cord atrophy, whereas CSF analysis typically identifies mild leucocytosis, moderately elevated protein levels, and detectable anti-HTLV-1 antibodies.
Recognizing the potential for confusion surrounding HTLV nomenclature is important. The term HTLV-3 was initially assigned to the virus now known as HIV before it was reclassified as a separate entity. Similarly, HTLV-4 was previously used synonymously with HIV-2. This overlap in terminology has contributed to clinical misunderstandings, with studies showing that more than 90% of diagnostic HTLV test requests were actually intended for HIV testing.[76]
Treatment / Management
The management of HTLV-1 infection remains challenging, as no curative therapy currently exists for the virus itself. Treatment strategies focus on controlling associated diseases such as ATLL and HAM/TSP, alleviating symptoms, and reducing the risk of transmission.
Currently, no approved treatment exists for HTLV. However, emerging evidence suggests that certain antiretroviral agents used in HIV therapy can be repurposed for HTLV. Laboratory studies have shown that tenofovir disoproxil is highly potent against HTLV, inhibiting the transmission of the virus.[47][77] Similar findings have been observed for dolutegravir, which targets the conserved integrase found in HTLV.[78] If confirmed in human studies, these agents could represent important advances in preventing mother-to-child HTLV transmission.
ATLL Management
Various combination chemotherapy regimens have been compared to highly active antiretroviral therapy protocols to improve morbidity and mortality in patients with ATLL. Limited evidence suggests that highly active antiretroviral therapy, including zidovudine and interferon-α, may be beneficial in lymphomatous ATLL, whereas multiagent chemotherapy appears more effective in acute, aggressive leukemic ATLL. Switching between these strategies is recommended for nonresponders.[43]
Intensive chemotherapy followed by allogenic hematopoietic stem-cell transplantation has shown promise in younger patients with aggressive ATLL. However, its broader use is limited, as many patients are ineligible due to age, with a median age at diagnosis of 68.[24] Long-term maintenance combination chemotherapy with vincristine/methotrexate, prednisolone, etoposide/cyclophosphamide (OPEC/MPEC) has been shown to improve survival and quality of life in older patients with ATLL.[79](B2)
HAM/TSP Management
Treatment options for HAP/TSP remain limited, and most therapies provide only modest benefit. The mainstay of management is symptomatic care. Corticosteroids have been widely used, with limited evidence suggesting a moderate benefit in slowing disease progression. Japanese centers have reported encouraging results with mogamulizumab, a monoclonal antibody that targets CCR4, noting a decrease in spasticity and an improvement in motor function.[80]
Antiviral therapies outside of research settings have been disappointing, failing to modify disease progression. For example, capsid inhibitors developed for HIV cannot be repurposed for HTLV despite both being retroviruses, as differences in viral envelope structure prevent effective drug targeting.
Vaccination
Currently, no vaccine exists for HTLV-1; however, several viral characteristics suggest that vaccine development may be feasible. These characteristics include the virus's low antigenic variability and evidence that natural immunity can develop in humans. Animal studies using envelope antigens have also produced encouraging results.[25] (B3)
The CCR4 receptor has been identified as a potential therapeutic target due to its central role in viral transmission and the host immune response. Ongoing research is exploring innovative approaches, including messenger RNA platforms, exosome-based delivery systems, and molecular clamp technologies, with emerging animal and laboratory studies yielding promising results.[81][82][83]
Differential Diagnosis
Distinguishing HTLV-1–related diseases from other hematologic and neurologic conditions can be difficult, as their clinical, histologic, and even immunophenotypic features often overlap. The careful integration of clinical history, laboratory testing, and molecular diagnostics is therefore essential to achieve an accurate diagnosis.
For ATLL, the differential centers around other T-cell malignancies, and deciphering these can be challenging. ATLL can mimic cutaneous T-cell lymphoma, as cutaneous features are similar both macroscopically and histologically, and even immunohistochemical profiles may be indistinguishable in some cases. The lymphomatous subtype can produce lymphadenopathy that morphologically resembles Hodgkin disease, with apparent Reed-Sternberg cells.[84] Examination of peripheral blood cells in asymptomatic patients with HTLV-1–infected individuals may reveal the characteristic flower cells of ATLL. Differentiating smoldering ATLL from asymptomatic HTLV-1 carriers without malignancy is particularly difficult, and PCR analysis to identify a malignant T-cell clone can aid in confirmation.
The principal differential diagnosis for HAM/TSP is multiple sclerosis, particularly the primary progressive form in patients from HTLV-1–endemic regions. Identifying the presence of HTLV-1 in CSF is essential for diagnosis. Other neurological diseases, including amyotrophic lateral sclerosis and conus medullaris syndrome, have also been associated with HTLV-1, but establishing causality in patients with concurrent HTLV-1 and neurological disease remains a significant challenge.
Prognosis
Acute HTLV-1 infection is typically undetected and often occurs early in life through vertical transmission. The prolonged and variable latency between infection and disease onset suggests that viral presence alone is insufficient for pathogenesis, with additional, poorly understood host or environmental factors likely involved. Prognostic understanding, therefore, remains incomplete. A meta-analysis demonstrated a 57% increased relative risk of all-cause mortality among individuals living with HTLV-1 infection compared to those living without, although the contribution of proviral load and other cofactors remains unclear.[46] These findings underscore the importance of prevention and transmission control in the absence of curative therapy.
ATLL carries a poor prognosis due to intrinsic chemoresistance and profound immunosuppression.[43] Outcomes depend on disease subtype, with the acute form associated with the shortest survival. In a US cohort of 195 patients followed for 16 years, the median survival was 4 months for acute ATLL (n=80), 10 months for lymphomatous ATLL (n=96), and 72 months for chronic or smoldering ATLL (n=12). Although survival appears more favorable in the indolent subtypes, these represent only 6% of the total study patients.[56]
The clinical course of HAM/TSP is highly variable, with few reliable predictors of progression beyond viral loads.[85] Most patients experience a gradual neurologic decline, whereas a minority progress to wheelchair dependence. In contrast, some individuals maintain near-normal function for decades, exhibiting only mild motor impairment.[61]
Complications
HTLV-1 is typically asymptomatic during the acute phase but leads to significant morbidity and mortality in approximately 5% of affected individuals through conditions including ATLL and HAM/TSP. These conditions generally develop years or decades after initial infection, contributing to delayed diagnosis and management. Although ATLL and HAM/TSP cause significant morbidity, the ability to predict disease onset, progression, and optimal treatment remains limited. Additional conditions associated with HTLV-1, including autoimmune, bronchial, and malignant manifestations, further contribute to long-term morbidity and impaired quality of life.
Deterrence and Patient Education
Patient awareness of HTLV-1, including knowledge of transmission routes and infection risk, remains limited even in populations with high prevalence.[86] Vulnerable groups, such as sex workers and people who inject drugs, are at increased risk of infection and often face significant barriers to healthcare access. There is a substantial need for public education addressing both vertical transmission through breastfeeding and horizontal transmission through sexual intercourse and needle-sharing.[87]
Regulatory policies have demonstrated value in reducing the transmission of HTLV-1 in endemic regions. Japan implemented HTLV-1 antibody screening in blood donations in 1986 and issued national recommendations advising women living with HTLV to avoid breastfeeding.[88] Since then, Japan has expanded towards nationwide screening of pregnant women and recommends exclusive formula feeding over short-term breastfeeding as the preferred preventive strategy.[89] Recognizing HTLV-1 as a sexually transmitted infection is also critical for improving provider awareness and encouraging consistent use of barrier methods to reduce transmission.
In high-prevalence settings, carefully designed education programs and shared decision-making between healthcare providers and patients are essential, particularly when counseling on testing, breastfeeding practices, and prevention strategies at the primary care level. Strengthening provider training and community engagement can foster earlier detection, reduce stigma, and promote informed, culturally sensitive approaches to HTLV-1 prevention and care.
Pearls and Other Issues
Key facts to keep in mind about HTLV-1 include the following:
- Retrovirus belonging to the Retroviridae family, genus Deltaretrovirus
- Enveloped, single-stranded, positive-sense RNA virus
- Transmission: Sexual contact, breastfeeding (vertical), blood transfusion, and needle sharing
- Endemic regions: Japan, the Caribbean, parts of Africa, Central/South America, and Australia
- Infects primarily CD4+ T lymphocytes
- Associated diseases:
- ATLL
- HAM/TSP
- Long latency period between infection and disease onset (years to decades)
- Pathogenesis involves the Tax protein (promotes cell proliferation and inhibits apoptosis)
- Diagnosis: Enzyme-linked immunosorbent assay screening → Western blot confirmation → PCR for proviral DNA
- No curative therapy; management is supportive and disease-specific
- Prevention: Screen blood products, avoid breastfeeding if infected, safe sex, and needle hygiene
- Not the same as HIV (different envelope, slower progression, and low viremia)
Enhancing Healthcare Team Outcomes
Effective management of HTLV-1 requires coordinated, interprofessional collaboration to optimize patient outcomes and safety. Clinicians and advanced practitioners are responsible for diagnosis, counseling, and long-term monitoring. In contrast, nurses play a key role in patient education, psychosocial support, and adherence to infection prevention strategies. Pharmacists contribute to ensuring the safe and evidence-based use of antivirals, immunomodulators, and symptomatic therapies, as well as monitoring for adverse effects or interactions. Public healthcare professionals and social workers play a crucial role in community education, risk reduction, and addressing the social determinants of health.
Ethical responsibilities include maintaining confidentiality, reducing stigma, and supporting informed decision-making, particularly regarding testing, breastfeeding, and reproductive choices. Regular interprofessional communication through shared care plans, multidisciplinary meetings, and culturally sensitive counseling enhances care coordination, improves early recognition of complications, and strengthens patient trust and engagement. Collectively, these strategies advance patient-centered care and improve long-term outcomes for individuals living with HTLV-1.
References
Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America. 1980 Dec:77(12):7415-9 [PubMed PMID: 6261256]
Tagaya Y, Matsuoka M, Gallo R. 40 years of the human T-cell leukemia virus: past, present, and future. F1000Research. 2019:8():. pii: F1000 Faculty Rev-228. doi: 10.12688/f1000research.17479.1. Epub 2019 Feb 28 [PubMed PMID: 30854194]
Araujo A, Hall WW. Human T-lymphotropic virus type II and neurological disease. Annals of neurology. 2004 Jul:56(1):10-9 [PubMed PMID: 15236397]
Kalyanaraman VS, Sarngadharan MG, Robert-Guroff M, Miyoshi I, Golde D, Gallo RC. A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science (New York, N.Y.). 1982 Nov 5:218(4572):571-3 [PubMed PMID: 6981847]
Chevalier SA, Durand S, Dasgupta A, Radonovich M, Cimarelli A, Brady JN, Mahieux R, Pise-Masison CA. The transcription profile of Tax-3 is more similar to Tax-1 than Tax-2: insights into HTLV-3 potential leukemogenic properties. PloS one. 2012:7(7):e41003. doi: 10.1371/journal.pone.0041003. Epub 2012 Jul 20 [PubMed PMID: 22911729]
Nejmeddine M, Barnard AL, Tanaka Y, Taylor GP, Bangham CR. Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse. The Journal of biological chemistry. 2005 Aug 19:280(33):29653-60 [PubMed PMID: 15975923]
Yoshie O. [CCR4, HTLV-1 infection, and ATL oncogenesis]. Uirusu. 2008 Dec:58(2):125-40 [PubMed PMID: 19374191]
Majorovits E, Nejmeddine M, Tanaka Y, Taylor GP, Fuller SD, Bangham CR. Human T-lymphotropic virus-1 visualized at the virological synapse by electron tomography. PloS one. 2008 May 28:3(5):e2251. doi: 10.1371/journal.pone.0002251. Epub 2008 May 28 [PubMed PMID: 18509526]
Kalinichenko S, Komkov D, Mazurov D. HIV-1 and HTLV-1 Transmission Modes: Mechanisms and Importance for Virus Spread. Viruses. 2022 Jan 14:14(1):. doi: 10.3390/v14010152. Epub 2022 Jan 14 [PubMed PMID: 35062355]
Wattel E, Vartanian JP, Pannetier C, Wain-Hobson S. Clonal expansion of human T-cell leukemia virus type I-infected cells in asymptomatic and symptomatic carriers without malignancy. Journal of virology. 1995 May:69(5):2863-8 [PubMed PMID: 7707509]
Bindhu M, Nair A, Lairmore MD. Role of accessory proteins of HTLV-1 in viral replication, T cell activation, and cellular gene expression. Frontiers in bioscience : a journal and virtual library. 2004 Sep 1:9():2556-76 [PubMed PMID: 15358581]
Level 3 (low-level) evidenceGross C, Thoma-Kress AK. Molecular Mechanisms of HTLV-1 Cell-to-Cell Transmission. Viruses. 2016 Mar 9:8(3):74. doi: 10.3390/v8030074. Epub 2016 Mar 9 [PubMed PMID: 27005656]
Mazurov D, Ilinskaya A, Heidecker G, Lloyd P, Derse D. Quantitative comparison of HTLV-1 and HIV-1 cell-to-cell infection with new replication dependent vectors. PLoS pathogens. 2010 Feb 26:6(2):e1000788. doi: 10.1371/journal.ppat.1000788. Epub 2010 Feb 26 [PubMed PMID: 20195464]
Giam CZ, Semmes OJ. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ. Viruses. 2016 Jun 16:8(6):. doi: 10.3390/v8060161. Epub 2016 Jun 16 [PubMed PMID: 27322308]
Nakano K, Watanabe T. HTLV-1 Rex: the courier of viral messages making use of the host vehicle. Frontiers in microbiology. 2012:3():330. doi: 10.3389/fmicb.2012.00330. Epub 2012 Sep 6 [PubMed PMID: 22973269]
Fuentes-González AM, Contreras-Paredes A, Manzo-Merino J, Lizano M. The modulation of apoptosis by oncogenic viruses. Virology journal. 2013 Jun 6:10():182. doi: 10.1186/1743-422X-10-182. Epub 2013 Jun 6 [PubMed PMID: 23741982]
Koralnik IJ, Boeri E, Saxinger WC, Monico AL, Fullen J, Gessain A, Guo HG, Gallo RC, Markham P, Kalyanaraman V. Phylogenetic associations of human and simian T-cell leukemia/lymphotropic virus type I strains: evidence for interspecies transmission. Journal of virology. 1994 Apr:68(4):2693-707 [PubMed PMID: 7908063]
Mahieux R, Chappey C, Georges-Courbot MC, Dubreuil G, Mauclere P, Georges A, Gessain A. Simian T-cell lymphotropic virus type 1 from Mandrillus sphinx as a simian counterpart of human T-cell lymphotropic virus type 1 subtype D. Journal of virology. 1998 Dec:72(12):10316-22 [PubMed PMID: 9811783]
Kazanji M, Mouinga-Ondémé A, Lekana-Douki-Etenna S, Caron M, Makuwa M, Mahieux R, Gessain A. Origin of HTLV-1 in hunters of nonhuman primates in Central Africa. The Journal of infectious diseases. 2015 Feb 1:211(3):361-5. doi: 10.1093/infdis/jiu464. Epub 2014 Aug 21 [PubMed PMID: 25147276]
Afonso PV, Cassar O, Gessain A. Molecular epidemiology, genetic variability and evolution of HTLV-1 with special emphasis on African genotypes. Retrovirology. 2019 Dec 16:16(1):39. doi: 10.1186/s12977-019-0504-z. Epub 2019 Dec 16 [PubMed PMID: 31842895]
Yanagihara R, Saitou N, Nerurkar VR, Song KJ, Bastian I, Franchini G, Gajdusek DC. Molecular phylogeny and dissemination of human T-cell lymphotropic virus type I viewed within the context of primate evolution and human migration. Cellular and molecular biology (Noisy-le-Grand, France). 1995:41 Suppl 1():S145-61 [PubMed PMID: 8574142]
Cassar O, Einsiedel L, Afonso PV, Gessain A. Human T-cell lymphotropic virus type 1 subtype C molecular variants among indigenous australians: new insights into the molecular epidemiology of HTLV-1 in Australo-Melanesia. PLoS neglected tropical diseases. 2013:7(9):e2418. doi: 10.1371/journal.pntd.0002418. Epub 2013 Sep 26 [PubMed PMID: 24086779]
Einsiedel L, Pham H, Wilson K, Walley R, Turpin J, Bangham C, Gessain A, Woodman RJ. Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians. PLoS neglected tropical diseases. 2018 Mar:12(3):e0006281. doi: 10.1371/journal.pntd.0006281. Epub 2018 Mar 12 [PubMed PMID: 29529032]
Nosaka K, Iwanaga M, Imaizumi Y, Ishitsuka K, Ishizawa K, Ishida Y, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Kawai K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, Tsukasaki K. Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey. Cancer science. 2017 Dec:108(12):2478-2486. doi: 10.1111/cas.13398. Epub 2017 Oct 8 [PubMed PMID: 28905463]
Level 2 (mid-level) evidencede Thé G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS research and human retroviruses. 1993 May:9(5):381-6 [PubMed PMID: 8318266]
Level 3 (low-level) evidenceEinsiedel L, Pham H, Talukder MRR, Liddle J, Taylor K, Wilson K, Jersmann H, Gessain A, Woodman R, Kaldor J. Pulmonary Disease Is Associated With Human T-Cell Leukemia Virus Type 1c Infection: A Cross-sectional Survey in Remote Aboriginal Communities. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021 Oct 5:73(7):e1498-e1506. doi: 10.1093/cid/ciaa1401. Epub [PubMed PMID: 32936911]
Level 2 (mid-level) evidenceEinsiedel L, Pham H, Talukder MR, Taylor K, Wilson K, Kaldor J, Gessain A, Woodman R. Very high prevalence of infection with the human T cell leukaemia virus type 1c in remote Australian Aboriginal communities: Results of a large cross-sectional community survey. PLoS neglected tropical diseases. 2021 Dec:15(12):e0009915. doi: 10.1371/journal.pntd.0009915. Epub 2021 Dec 8 [PubMed PMID: 34879069]
Level 2 (mid-level) evidenceMaloney EM, Cleghorn FR, Morgan OS, Rodgers-Johnson P, Cranston B, Jack N, Blattner WA, Bartholomew C, Manns A. Incidence of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica and Trinidad. Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association. 1998 Feb 1:17(2):167-70 [PubMed PMID: 9473019]
Tsukasaki K. Adult T-cell leukemia-lymphoma. Hematology (Amsterdam, Netherlands). 2012 Apr:17 Suppl 1():S32-5. doi: 10.1179/102453312X13336169155330. Epub [PubMed PMID: 22507774]
Paiva AM, Assone T, Haziot MEJ, Smid J, Fonseca LAM, Luiz ODC, de Oliveira ACP, Casseb J. Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV-1-infected offspring. Scientific reports. 2018 May 17:8(1):7742. doi: 10.1038/s41598-018-25939-y. Epub 2018 May 17 [PubMed PMID: 29773807]
Itabashi K, Miyazawa T, Nerome Y, Sekizawa A, Moriuchi H, Saito S, Yonemoto N. Issues of infant feeding for postnatal prevention of human T-cell leukemia/lymphoma virus type-1 mother-to-child transmission. Pediatrics international : official journal of the Japan Pediatric Society. 2021 Mar:63(3):284-289. doi: 10.1111/ped.14356. Epub 2021 Feb 27 [PubMed PMID: 32574414]
Itabashi K, Miyazawa T. Mother-to-Child Transmission of Human T-Cell Leukemia Virus Type 1: Mechanisms and Nutritional Strategies for Prevention. Cancers. 2021 Aug 14:13(16):. doi: 10.3390/cancers13164100. Epub 2021 Aug 14 [PubMed PMID: 34439253]
Boostani R, Sadeghi R, Sabouri A, Ghabeli-Juibary A. Human T-lymphotropic virus type I and breastfeeding; systematic review and meta-analysis of the literature. Iranian journal of neurology. 2018 Oct 7:17(4):174-179 [PubMed PMID: 31210902]
Level 1 (high-level) evidenceTakezaki T, Tajima K, Komoda H, Imai J. Incidence of human T lymphotropic virus type I seroconversion after age 40 among Japanese residents in an area where the virus is endemic. The Journal of infectious diseases. 1995 Mar:171(3):559-65 [PubMed PMID: 7876601]
Stuver SO, Tachibana N, Okayama A, Shioiri S, Tsunetoshi Y, Tsuda K, Mueller NE. Heterosexual transmission of human T cell leukemia/lymphoma virus type I among married couples in southwestern Japan: an initial report from the Miyazaki Cohort Study. The Journal of infectious diseases. 1993 Jan:167(1):57-65 [PubMed PMID: 8418183]
Bartholomew C, Jack N, Edwards J, Charles W, Corbin D, Cleghorn FR, Blattner WA. HTLV-I serostatus of mothers of patients with adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. Journal of human virology. 1998 May-Jun:1(4):302-5 [PubMed PMID: 10195256]
Level 2 (mid-level) evidenceTake H, Umemoto M, Kusuhara K, Kuraya K. Transmission routes of HTLV-I: an analysis of 66 families. Japanese journal of cancer research : Gann. 1993 Dec:84(12):1265-7 [PubMed PMID: 8294217]
Krämer A, Maloney EM, Morgan OS, Rodgers-Johnson P, Manns A, Murphy EL, Larsen S, Cranston B, Murphy J, Benichou J. Risk factors and cofactors for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica. American journal of epidemiology. 1995 Dec 1:142(11):1212-20 [PubMed PMID: 7485068]
Level 2 (mid-level) evidenceMurphy EL. Infection with human T-lymphotropic virus types-1 and -2 (HTLV-1 and -2): Implications for blood transfusion safety. Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine. 2016 Feb:23(1):13-9. doi: 10.1016/j.tracli.2015.12.001. Epub 2016 Jan 5 [PubMed PMID: 26778839]
Yamauchi J, Yamano Y, Yuzawa K. Risk of Human T-Cell Leukemia Virus Type 1 Infection in Kidney Transplantation. The New England journal of medicine. 2019 Jan 17:380(3):296-298. doi: 10.1056/NEJMc1809779. Epub [PubMed PMID: 30650320]
Tajima K. Malignant lymphomas in Japan: epidemiological analysis of adult T-cell leukemia/lymphoma (ATL). Cancer metastasis reviews. 1988 Nov:7(3):223-41 [PubMed PMID: 3067901]
Level 2 (mid-level) evidenceLee DK, Kim BC, Brady JN, Jeang KT, Kim SJ. Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking the association of Smad proteins with Smad-binding element. The Journal of biological chemistry. 2002 Sep 13:277(37):33766-75 [PubMed PMID: 12097320]
Kchour G, Makhoul NJ, Mahmoudi M, Kooshyar MM, Shirdel A, Rastin M, Rafatpanah H, Tarhini M, Zalloua PA, Hermine O, Farid R, Bazarbachi A. Zidovudine and interferon-alpha treatment induces a high response rate and reduces HTLV-1 proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran. Leukemia & lymphoma. 2007 Feb:48(2):330-6 [PubMed PMID: 17325893]
Shah V, Bendele A, Dines JS, Kestler HK, Hollinger JO, Chahine NO, Hee CK. Dose-response effect of an intra-tendon application of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in a rat Achilles tendinopathy model. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2013 Mar:31(3):413-20. doi: 10.1002/jor.22222. Epub 2012 Aug 29 [PubMed PMID: 22933269]
Level 3 (low-level) evidenceMcLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annual review of immunology. 2019 Apr 26:37():457-495. doi: 10.1146/annurev-immunol-041015-055318. Epub 2019 Jan 24 [PubMed PMID: 30676822]
Schierhout G, McGregor S, Gessain A, Einsiedel L, Martinello M, Kaldor J. Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies. The Lancet. Infectious diseases. 2020 Jan:20(1):133-143. doi: 10.1016/S1473-3099(19)30402-5. Epub 2019 Oct 21 [PubMed PMID: 31648940]
Level 1 (high-level) evidencePasquier A, Alais S, Roux L, Thoulouze MI, Alvarez K, Journo C, Dutartre H, Mahieux R. How to Control HTLV-1-Associated Diseases: Preventing de Novo Cellular Infection Using Antiviral Therapy. Frontiers in microbiology. 2018:9():278. doi: 10.3389/fmicb.2018.00278. Epub 2018 Mar 13 [PubMed PMID: 29593659]
Futsch N, Mahieux R, Dutartre H. HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment. Viruses. 2017 Dec 21:10(1):. doi: 10.3390/v10010001. Epub 2017 Dec 21 [PubMed PMID: 29267225]
Martin F, Taylor GP, Jacobson S. Inflammatory manifestations of HTLV-1 and their therapeutic options. Expert review of clinical immunology. 2014 Nov:10(11):1531-46. doi: 10.1586/1744666X.2014.966690. Epub [PubMed PMID: 25340428]
Nadella MV, Shu ST, Dirksen WP, Thudi NK, Nadella KS, Fernandez SA, Lairmore MD, Green PL, Rosol TJ. Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: implications for transformation. Retrovirology. 2008 Jun 9:5():46. doi: 10.1186/1742-4690-5-46. Epub 2008 Jun 9 [PubMed PMID: 18541021]
Gupta VK, El-Jawahri A, Orkev G, Johnson MH, Weinberg J, Goodrich C, Janakiram M, Sloan JM. Impact of Human T Cell Lymphotropic Virus Type 1 and 2 Infection on Survival Following Stem Cell Transplantation. Transplantation and cellular therapy. 2022 May:28(5):276.e1-276.e5. doi: 10.1016/j.jtct.2022.01.023. Epub 2022 Feb 2 [PubMed PMID: 35123118]
Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W Jr, O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Jan 20:27(3):453-9. doi: 10.1200/JCO.2008.18.2428. Epub 2008 Dec 8 [PubMed PMID: 19064971]
Level 3 (low-level) evidenceDesai A, Fe A, Desai A, Ilowite J, Cunha BA, Mathew JP. A Case of Pneumonia Caused by Pneumocystis Jirovecii and Cryptococcus Neoformans in a Patient with HTLV-1 Associated Adult T- Cell Leukemia/Lymphoma: Occam's Razor Blunted. Connecticut medicine. 2016 Feb:80(2):81-3 [PubMed PMID: 27024978]
Level 3 (low-level) evidenceKawano N, Nagahiro Y, Yoshida S, Tahara Y, Himeji D, Kuriyama T, Tochigi T, Nakaike T, Shimokawa T, Yamashita K, Ochiai H, Marutsuka K, Mashiba K, Shimoda K, Teshima T, Kikuchi I. Clinical features and treatment outcomes of opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia-lymphoma (ATL) at a single institution from 2006 to 2016. Journal of clinical and experimental hematopathology : JCEH. 2019:59(4):156-167. doi: 10.3960/jslrt.18032. Epub [PubMed PMID: 31866618]
Mahieux R, Gessain A. HTLV-1 and associated adult T-cell leukemia/lymphoma. Reviews in clinical and experimental hematology. 2003 Dec:7(4):336-61 [PubMed PMID: 15129647]
Malpica L, Pimentel A, Reis IM, Gotuzzo E, Lekakis L, Komanduri K, Harrington T, Barber GN, Ramos JC. Epidemiology, clinical features, and outcome of HTLV-1-related ATLL in an area of prevalence in the United States. Blood advances. 2018 Mar 27:2(6):607-620. doi: 10.1182/bloodadvances.2017011106. Epub [PubMed PMID: 29545256]
Level 3 (low-level) evidenceBangham CR, Araujo A, Yamano Y, Taylor GP. HTLV-1-associated myelopathy/tropical spastic paraparesis. Nature reviews. Disease primers. 2015 Jun 18:1():15012. doi: 10.1038/nrdp.2015.12. Epub 2015 Jun 18 [PubMed PMID: 27188208]
Araujo AQ, Silva MT. The HTLV-1 neurological complex. The Lancet. Neurology. 2006 Dec:5(12):1068-76 [PubMed PMID: 17110288]
Coler-Reilly AL, Yagishita N, Suzuki H, Sato T, Araya N, Inoue E, Takata A, Yamano Y. Nation-wide epidemiological study of Japanese patients with rare viral myelopathy using novel registration system (HAM-net). Orphanet journal of rare diseases. 2016 May 25:11(1):69. doi: 10.1186/s13023-016-0451-x. Epub 2016 May 25 [PubMed PMID: 27225443]
Level 2 (mid-level) evidenceRaza SM, Pyatt JR. Nocturnal hypertension and autonomic dysfunction due to human T-lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). International journal of cardiology. 2006 Mar 8:107(3):424-6 [PubMed PMID: 16503269]
Level 3 (low-level) evidenceYamano Y, Sato T. Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis. Frontiers in microbiology. 2012:3():389. doi: 10.3389/fmicb.2012.00389. Epub 2012 Nov 9 [PubMed PMID: 23162542]
McGill NK, Vyas J, Shimauchi T, Tokura Y, Piguet V. HTLV-1-associated infective dermatitis: updates on the pathogenesis. Experimental dermatology. 2012 Nov:21(11):815-21. doi: 10.1111/exd.12007. Epub [PubMed PMID: 23163646]
Kamoi K, Mochizuki M. HTLV-1 uveitis. Frontiers in microbiology. 2012:3():270. doi: 10.3389/fmicb.2012.00270. Epub 2012 Jul 24 [PubMed PMID: 22837757]
Einsiedel L, Fernandes L, Spelman T, Steinfort D, Gotuzzo E. Bronchiectasis is associated with human T-lymphotropic virus 1 infection in an Indigenous Australian population. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2012 Jan 1:54(1):43-50. doi: 10.1093/cid/cir766. Epub 2011 Nov 17 [PubMed PMID: 22095566]
Level 2 (mid-level) evidenceHonarbakhsh S, Taylor GP. High prevalence of bronchiectasis is linked to HTLV-1-associated inflammatory disease. BMC infectious diseases. 2015 Jul 6:15():258. doi: 10.1186/s12879-015-1002-0. Epub 2015 Jul 6 [PubMed PMID: 26143070]
Filippone C, Bassot S, Betsem E, Tortevoye P, Guillotte M, Mercereau-Puijalon O, Plancoulaine S, Calattini S, Gessain A. A new and frequent human T-cell leukemia virus indeterminate Western blot pattern: epidemiological determinants and PCR results in central African inhabitants. Journal of clinical microbiology. 2012 May:50(5):1663-72. doi: 10.1128/JCM.06540-11. Epub 2012 Mar 7 [PubMed PMID: 22403426]
Level 2 (mid-level) evidenceSaghafi M, Rezaieyazdi Z, Nabavi S, Mirfeizi Z, Sahebari M, Salari M. HTLV-1 seroprevalance in sarcoidosis. A clinical and laboratory study in northeast of Iran. International journal of rheumatic diseases. 2018 Jun:21(6):1309-1313. doi: 10.1111/1756-185X.13009. Epub 2017 Feb 9 [PubMed PMID: 28185411]
Li HC, Biggar RJ, Miley WJ, Maloney EM, Cranston B, Hanchard B, Hisada M. Provirus load in breast milk and risk of mother-to-child transmission of human T lymphotropic virus type I. The Journal of infectious diseases. 2004 Oct 1:190(7):1275-8 [PubMed PMID: 15346338]
Fuchi N, Miura K, Tsukiyama T, Sasaki D, Ishihara K, Tsuruda K, Hasegawa H, Miura S, Yanagihara K, Masuzaki H. Natural Course of Human T-Cell Leukemia Virus Type 1 Proviral DNA Levels in Carriers During Pregnancy. The Journal of infectious diseases. 2018 Apr 11:217(9):1383-1389. doi: 10.1093/infdis/jiy017. Epub [PubMed PMID: 29346571]
Kuramitsu M, Momose H, Uchida Y, Ishitsuka K, Kubota R, Tokunaga M, Utsunomiya A, Umekita K, Hashikura Y, Nosaka K, Koh K-R, Nakamura H, Sagara Y, Sobata R, Satake M, Nagata K, Hasegawa Y, Sasaki D, Hasegawa H, Sato T, Yamano Y, Hiraga K, Tezuka K, Ikebe E, Matsuoka S, Okuma K, Watanabe T, Miura K, Hamaguchi I. Performance evaluation of Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test for different diagnostic situations. Microbiology spectrum. 2023 Dec 12:11(6):e0207823. doi: 10.1128/spectrum.02078-23. Epub 2023 Nov 15 [PubMed PMID: 37966220]
Teoh LS, Guiraud V, Ong H, Du Y, Zhao Z, Gautheret-Dejean A, Xu N. A novel high-performance rapid screening test for the detection of total HTLV-I and HTLV-II antibodies in HTLV-I/II infected patients. BMC infectious diseases. 2024 Aug 26:24(1):860. doi: 10.1186/s12879-024-09791-2. Epub 2024 Aug 26 [PubMed PMID: 39187753]
Bittencourt AL, Andrade AC, Requião C, Arruda MD, Araújo I. Prolonged lymphocytosis as the first manifestation of Hodgkin-like adult T-cell leukemia/lymphoma. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases. 2017 Jan-Feb:21(1):119-122. doi: 10.1016/j.bjid.2016.09.005. Epub 2016 Oct 24 [PubMed PMID: 27789281]
Peloponese JM Jr, Kinjo T, Jeang KT. Human T-cell leukemia virus type 1 Tax and cellular transformation. International journal of hematology. 2007 Aug:86(2):101-6 [PubMed PMID: 17875521]
Ishitsuka K, Tamura K. Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. The Lancet. Oncology. 2014 Oct:15(11):e517-26. doi: 10.1016/S1470-2045(14)70202-5. Epub [PubMed PMID: 25281470]
De Castro-Costa CM, Araújo AQ, Barreto MM, Takayanagui OM, Sohler MP, da Silva EL, de Paula SM, Ishak R, Ribas JG, Rovirosa LC, Carton H, Gotuzzo E, Hall WW, Montano S, Murphy EL, Oger J, Remondegui C, Taylor GP. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). AIDS research and human retroviruses. 2006 Oct:22(10):931-5 [PubMed PMID: 17067261]
Siemieniuk RA, Fonseca K, Gill MJ. Using root cause analysis and form redesign to reduce incorrect ordering of HIV tests. Joint Commission journal on quality and patient safety. 2012 Nov:38(11):506-12 [PubMed PMID: 23173397]
Level 2 (mid-level) evidenceHill SA, Lloyd PA, McDonald S, Wykoff J, Derse D. Susceptibility of human T cell leukemia virus type I to nucleoside reverse transcriptase inhibitors. The Journal of infectious diseases. 2003 Aug 1:188(3):424-7 [PubMed PMID: 12870124]
Kalemera MD, Maher AK, Dominguez-Villar M, Maertens GN. Cell Culture Evaluation Hints Widely Available HIV Drugs Are Primed for Success if Repurposed for HTLV-1 Prevention. Pharmaceuticals (Basel, Switzerland). 2024 Jun 5:17(6):. doi: 10.3390/ph17060730. Epub 2024 Jun 5 [PubMed PMID: 38931397]
Nakamura D, Yoshimitsu M, Tabuchi T, Arima N, Hayashida M, Inoue H, Matsushita K, Matsumoto T, Arima N, Ishitsuka K. Treatment of aggressive adult T-cell leukemia/lymphoma: a retrospective study in a hospital located in HTLV-1 highly endemic area. International journal of hematology. 2020 Feb:111(2):234-240. doi: 10.1007/s12185-019-02769-w. Epub 2019 Nov 12 [PubMed PMID: 31721034]
Level 2 (mid-level) evidenceSato T, Coler-Reilly ALG, Yagishita N, Araya N, Inoue E, Furuta R, Watanabe T, Uchimaru K, Matsuoka M, Matsumoto N, Hasegawa Y, Yamano Y. Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. The New England journal of medicine. 2018 Feb 8:378(6):529-538. doi: 10.1056/NEJMoa1704827. Epub [PubMed PMID: 29414279]
Ratner L. A role for an HTLV-1 vaccine? Frontiers in immunology. 2022:13():953650. doi: 10.3389/fimmu.2022.953650. Epub 2022 Sep 8 [PubMed PMID: 36159878]
Tu JJ, King E, Maksimova V, Smith S, Macias R, Cheng X, Vegesna T, Yu L, Ratner L, Green PL, Niewiesk S, Richner JM, Panfil AR. An HTLV-1 envelope mRNA vaccine is immunogenic and protective in New Zealand rabbits. Journal of virology. 2024 Feb 20:98(2):e0162323. doi: 10.1128/jvi.01623-23. Epub 2024 Jan 9 [PubMed PMID: 38193692]
Pinto DO, Al Sharif S, Mensah G, Cowen M, Khatkar P, Erickson J, Branscome H, Lattanze T, DeMarino C, Alem F, Magni R, Zhou W, Alais S, Dutartre H, El-Hage N, Mahieux R, Liotta LA, Kashanchi F. Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread. Retrovirology. 2021 Feb 23:18(1):6. doi: 10.1186/s12977-021-00550-8. Epub 2021 Feb 23 [PubMed PMID: 33622348]
Chen YP, Wu ZJ, Liu W, Lu JP, Wang JC, Zhu WF, Chen FF, Zhong LH, Chen G. [Clinicopathological characteristics of adult T cell leukemia/lymphoma]. Zhonghua bing li xue za zhi = Chinese journal of pathology. 2019 Jan 8:48(1):11-16. doi: 10.3760/cma.j.issn.0529-5807.2019.01.003. Epub [PubMed PMID: 30641639]
Sato T, Yagishita N, Tamaki K, Inoue E, Hasegawa D, Nagasaka M, Suzuki H, Araya N, Coler-Reilly A, Hasegawa Y, Tsuboi Y, Takata A, Yamano Y. Proposal of Classification Criteria for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Disease Activity. Frontiers in microbiology. 2018:9():1651. doi: 10.3389/fmicb.2018.01651. Epub 2018 Jul 25 [PubMed PMID: 30090093]
Ramos JM, Milla A, Sánchez V, Vergés M, Toro C, Gutiérrez F. [Prenatal screening for Trypanosoma cruzi and human T lymphotropic virus types 1 and 2 in pregnant Latin American women]. Enfermedades infecciosas y microbiologia clinica. 2009 Mar:27(3):165-7. doi: 10.1016/j.eimc.2008.04.006. Epub 2009 Feb 11 [PubMed PMID: 19306717]
Level 3 (low-level) evidenceCampos KR, Gonçalves MG, Caterino-de-Araujo A. Short Communication: Failures in Detecting HTLV-1 and HTLV-2 in Patients Infected with HIV-1. AIDS research and human retroviruses. 2017 Apr:33(4):382-385. doi: 10.1089/AID.2016.0191. Epub 2016 Nov 14 [PubMed PMID: 27750018]
Sagara Y, Nakamura H, Satake M, Matsuzaki K. Detection of early phase human T-cell leukemia virus type 1 and 2 infection with an improved confirmatory test. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2023 Nov:168():105598. doi: 10.1016/j.jcv.2023.105598. Epub 2023 Sep 20 [PubMed PMID: 37748321]
Yonemoto N, Suzuki S, Sekizawa A, Hoshi S, Sagara Y, Itabashi K. Implementation of nationwide screening of pregnant women for HTLV-1 infection in Japan: analysis of a repeated cross-sectional study. BMC public health. 2020 Jul 22:20(1):1150. doi: 10.1186/s12889-020-09258-4. Epub 2020 Jul 22 [PubMed PMID: 32698800]
Level 2 (mid-level) evidence