Human T Cell Lymphotropic Virus

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Continuing Education Activity

Human T Cell lymphotropic viruses (HTLV) are a family of retroviruses. Currently, four types of this virus have been identified which are known to infect humans with a pathological consequence: HTLV-1, HTLV-2, HTLV-3, and HTLV-4. These viruses are known for their oncogenic potential as well as etiology in other disease processes. Although a significant number who become infected with these viruses will remain asymptomatic, a small proportion may develop malignant, inflammatory, or opportunistic diseases. This article will focus primarily on HTLV-1 given that this is the most clinically relevant and well-studied of the four viruses. HTLV-1 is endemic throughout the world however high infection rates are now emerging in intravenous drug users in the United States. This activity reviews the epidemiology of HTLV-1, highlights the potential secondary diseases caused by this oncovirus, and considers possible treatment options for both the virus and these conditions. It also highlights the importance of the interprofessional team in evaluating and treating patients suffering from this infection.


  • Summarise the virology of Human T cell lymphotropic virus-1.
  • Outline the known routes of human transmission in Human T cell lymphotropic virus-1.
  • Identify the common clinical conditions of adult T Cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) which are associated with human T cell lymphotropic virus-1.
  • Review potential treatment options for conditions related to the human T cell lymphotropic virus-1 and interprofessional team strategies to prevent virus transmission.


Human T-lymphotropic viruses (HTLV) are a family of human retroviruses recognized as oncoviruses. They are known for their causation of other immunosuppressive and inflammatory diseases. HTLV-1 is the most clinically significant of this family and was the first demonstrable case of a pathogen capable of inducing malignant disease. HTLV-1 is now widely believed to be one of the most potent oncogenic agents in humans.[1] Although approximately 95% of those who contract HTLV-1 will be asymptomatic, the remaining 5% may develop fatal malignant, inflammatory, or opportunistic disease.


Human T-lymphotropic virus-1 is an enveloped single-stranded RNA retrovirus. Its genomic organization is typical of the Retroviridae family; it has two long terminal repeat (LTR) sequences with the gag, pol, and env genes. HTLV-1 has an additional identifying region pX, which encodes for several regulatory proteins, one of which is Tax. This Tax protein is strongly implicated in the pathophysiology of HTLV-1.[2]

HTLV-1 infection occurs primarily and most efficiently via the transmission of infected lymphocytes (though free viral particles have been demonstrated to infect dendritic cells).[3] Once infected, CD4+ cells produce CCL22 (a CCR4 ligand), which in turn attracts CCR4-expressing CD4 cells, termed the “virological synapse.”[4] This process, therefore, potentiates preferential transmission of HTLV-1 within a CCR4+ CD4+ T cell (TC) population. Although both viruses infect TCs, there are several key differences between the virology and, therefore, the ultimate pathophysiology of HTLV-1 and human immunodeficiency virus (HIV). This mode of the cell to cell transmission is an example of one such difference and results in the very low viremia associated with HTLV-1 in contrast to the high viral loads of HIV.

A second characteristic feature of HTLV-1 is its high genetic stability, which is ensured by its mode of replication.[5] Upon cell entry, the HTLV-1 genome is reverse transcribed, the DNA product of which is inserted into the host genome. After this, the virus can be replicated in two ways: firstly, via infectious replication whereupon, the re-expression of this integrated provirus produces a new intracellular virion, and secondly, when the cell undergoes mitotic division the integrated provirus replicates. Viral replication is associated irrevocably with host cellular reproduction as opposed to independent viral DNA polymerase.[6] This yields a relatively low viral replication rate with high fidelity of transcription. The result is a stable genetic product (sharply dissimilar to that of HIV), which is protected from immune escape.[7]

HTLV-1 is able to regulate its own transcription and, therefore, transiently expresses gene products that may contribute to evasion of the host immune control.[8] Two regulatory proteins facilitate this: the aforementioned Tax (activates transcription) and Rex (suppresses transcription).[9] Integration of the provirus and translation of viral products is associated with cellular proliferation and enhanced survival, thereby conferring viral protection. Importantly HTLV-1 infection does not result in cellular death, unlike HIV, but instead, TCs evade apoptosis and readily transform.[10]


Human T-lymphotropic virus-1 is estimated to infect 10-20 million persons worldwide.[11] Though the true number is difficult to accurately estimate due to the lack of systematic serological testing. A global endemic of HTLV-1 and 2 has long been recognized; however, an epidemic appears to be emerging within intravenous drug users across the United States.[12] Japan is the most endemic country for HTLV-1 and reports more adult T-cell lymphoma/leukemia (ATLL) cases annually than any other country.[11] Men are more susceptible to ATLL, whereas more female cases of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) are reported than males.[13]

There are three major routes of HTLV-1 transmission: vertical transmission from mother to child via breastmilk (the most common route), sexual intercourse, and blood transfusions.[14] HTLV-1 has been isolated in breastmilk, and breastfed children are four times more likely to be infected than bottle-fed infants from infected mothers.[15] A longer duration of breastfeeding increases the risk of transmission, and it has been proposed that maternal antibodies transferred during pregnancy protect babies for some months post-natally. The risk to bottle-fed children is significantly lower but not negated entirely: 0.6% at one year and 4.6% at four years.[16]

Sexual transmission of HTLV-1 is more efficient from men to women than from women to men at a rate of approximately 5:1. HAM/TSP is associated with sexual transmission and blood transfusion.[17] Risk factors for HAM/TSP include young age at the first sexual encounter and more than five sexual partners over a lifetime.[18] These risk factors are not identified in ATLL, which is more commonly associated with vertical transmission of HTLV-1.

Transfusion of infected blood is associated with a high risk of rapid seroconversion.[19] This risk is significantly reduced in countries that screen for HTLV-1, such as the US, Canada, UK, Australia, New Zealand, and Brazil. Organ donations in the US are also screened for both HTLV-1 and HTLV-2. There is limited data on this route of transmission, but small studies suggest that the risk of infection is high in a seronegative recipient and a seropositive donor. One study of 10 patients found that 7 seroconverted within 4.5 years and 4 developed HAM/TSP.[20]

The risk of occupational exposure in healthcare workers via needle stick injuries has never been quantified but is not thought to be significant, and no post-exposure prophylaxis has been validated.


Human T-lymphotropic virus-1 is commonly implicated in two distinct diseases: adult T-cell lymphoma (ATLL) in approximately 4% of infected individuals and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in 2%.[13] The difference in gender-predominance is well-accepted; men are more susceptible to ATLL, whereas more HTLV-1 infected women develop HAM/TSP.[21] These two conditions are also associated with different modes of viral transmission; ATLL with vertical transmission and HAM/TSP with blood transfusion. These modes of transmission are associated with different ages; therefore, it is likely that the age at which a person becomes infected is significant. No significant difference in strains of HTLV-1 has been identified; therefore, it is believed that a combination of co-factors and host response is responsible for the clinical outcome.

Viral gene products interact with transcription factors of the host and mediate cellular transformation and, therefore, oncogenesis. Tax is one of the main viral proteins which mediates this disruption via several routes. Tax upregulates survival pathways for T cells (through IL-2 and IL-15) and promotes inhibition of apoptosis (through stimulation of Bcl-XL, which prevents caspase activation) whilst suppressing cell cycle control and DNA repair. Intracellularly NF-KB promotes inflammation, and HTLV-1 has been shown to induce class-switching of T cells to skew a T helper cell (ThC)-1 profile, which is further pro-inflammatory.[22] High levels of circulating plasma vascular endothelial growth factor (VEGF) promote angiogenesis.[23] Both HTLV-1 and HTLV-2 have demonstrated in vitro the ability to transform human lymphocytes to be self-sustaining.

A humoral immune response is prompted in response to HTLV-1 infection, and antibodies are produced in response to viral Gag, Env, and Tax proteins. The cellular response is coordinated by HTLV-specific cytotoxic lymphocytes, which largely recognize epitopes from the Tax protein. They are present in high numbers in those with an asymptomatic infection and therefore appear to be important in the control of HTLV-1.[24]

The interaction of the host immune response with HTLV-1-encoded genes has also been demonstrated to facilitate an environment of immunosuppression. Acute infection is noted to promote an IL-10-dominant cytokine profile, which is known to suppress the T cell response. CD8 T-cell exhaustion is secondary to persistent viral proliferation results in failure of virus-specific suppression: a mechanism believed to be important in both chronic viral-mediated immunosuppression and oncogenesis.[25]

History and Physical

Acute human T-lymphotropic virus-1 infections are rarely identified or diagnosed as the initial infection is so commonly asymptomatic.[26] Suspected or confirmed cases may prompt investigation into a mode of transmissions such as a recent blood transfusion or a nursing infant whose mother is from an endemic area. No treatment is indicated in the context of acute HTLV-1 infection, but lifestyle advice is prudent regarding breastfeeding, safe sex, and vigilance of evolving clinical symptoms.

ATLL is defined as a neoplastic clonal expansion of CD4+ cells infected with HTLV-1. The lifetime risk of developing ATLL in HTLV-1 infected individuals appears to be approximately 4%, and there is often a lag of up to three decades between initial infection and malignant transformation.[27]

Presenting signs and symptoms of ATLL include generalized lymphadenopathy, cutaneous lesions, hepatosplenomegaly, and immunosuppressed state heralded by established opportunistic infections. Paraneoplastic hypercalcemia is usually present at the time of ATLL diagnosis and may be caused by tumor necrosis factor-beta or parathyroid hormone-related protein (PTHrP). Bone turnover is accelerated, and lytic bone lesions are often present.[28]

The diversity of clinical presentation and disease progression of ATLL necessitates sub-classification into four categories: acute, lymphomatous, chronic, and smoldering.[29]

Acute: The most common of these is the acute type, which is associated with the worst prognosis (median survival from diagnosis is six months) and accounts for 55% of ATLL cases. Clinical features include skin lesions, bone pain caused by hypercalcemia and lytic bone lesions, and pulmonary symptoms with infiltrates present on chest imaging. Pulmonary features may be caused by primary disease or opportunistic infections, which are present in 30% of patients at presentation. Commonly encountered opportunistic organisms include Pneumocystis jirovecii (causing PCP pneumonia often seen in AIDS patients), Cryptococcus neoformans causing occult meningitis,[30] Herpes zoster and Strongyloides stercoralis infestation.[31]

Lymphomatous: This form accounts for 20% of cases, and clinical features include massive lymphadenopathy and splenomegaly with the absence of circulating tumor cells.[32] Skin lesions may also be present, and patients are often hypercalcemic at presentation with resultant complications, including renal injury and neuropsychiatric disturbance.

Chronic: This type occurs in a further 20% of ATLL cases and has a more indolent disease course compared to the acute and lymphomatous sub-types with a median survival of two years.[29]

Smoldering: Is the rarest form of ATLL accounting for only 5% of disease burden. Cutaneous features are often present, but these are milder than those seen in the acute sub-type. Respiratory or gastrointestinal symptoms are absent. For the diagnosis of this sub-type, fewer than 5% of peripheral CD4+ T cells are affected.[33] Median survival without treatment is three years. 

HAM/TSP: Characterised as chronic myelopathy, which develops and progresses over the years, although cases of faster deterioration have been described, and this is hypothesized to correlate positively with a high viral load.[34]

The typical presentation is one of slowly progressive paraparesis with associated spasticity. First physical signs are usually in the lower limbs, but upper limb involvement may follow. Limb weakness is more marked proximally.[35] Widespread pyramidal signs are almost always seen. Sensory signs are usually subtle, and vibration sensation is often the first indication of a sensory defect. A clear sensory level is rare. The thoracic cord is the site most commonly affected by viral-mediated inflammation. Additionally, many patients report severe thoracolumbar back pain. This is one of the most debilitating features and is notoriously difficult to control, though neuropathic agents should be used with analgesics.[36]

Autonomic dysfunction is well-described in HAM/TSP. These patients can suffer from orthostatic hypotension, and hyperhidrosis/hypohidrosis can significantly affect patients’ quality of life.[37] Bladder dysfunction is a recognized early feature; patients report urgency, which progresses to urinary incontinence. Cognitive function is classically intact. The clinical course of HAM/TSP is highly variable, with some patients being rapidly confined to a wheelchair while others with only minimal weakness decades after their diagnosis. Reliable methods to predict disease progression remain elusive.[38]

Other Neurological Disease: In addition to these two main diseases caused by HTLV-1 described above, HTLV-1 is also linked to a myriad of other neurological diseases, including sub-acute meningitis, encephalitis, amyotrophic lateral sclerosis syndromes, and conus medullaris syndrome.[35]

Dermatological: HTLV-1 is associated with infective dermatitis, usually affecting the face, scalp, and flexures of infected children. Clinically it is characterized by an eczematous rash that frequently is infected by secondary organisms such as Staphylococci and Streptococci.[39] This condition usually improves throughout adolescence and is unusual in adults.

Ophthalmological: HTLV-1-associated uveitis presents with floaters, and blurred vision frequently affecting both eyes and is more common in patients under 50 years of age. On examination, the anterior chamber is cloudy with cells, and there may be retinal involvement too with hemorrhages and exudates. These patients respond well to topical steroid therapy but frequently flare when this has weaned necessitating long-term treatment with increased risk of steroid-induced glaucoma.[40]

Rheumatological: A significant number of autoimmune diseases are observed more frequently in HTLV-1 infected patients, including polymyositis, Sjögren syndrome, and Raynaud disease.[41]

Pulmonary: Bronchiolar disease occurs with a significantly higher incidence in HTLV-1 affected individuals compared to the background population. This has been observed in a large prospective Australian study that found that of patients hospitalized with bronchiectasis, 60% of these patients were identified to be infected with HTLV-1 compared to a general population prevalence of 10%.[42] A similar UK study of HTLV-1 affected patients found that 3% of total patients had CT changes indicative of bronchiectasis versus the 0.1% prevalence of bronchiectasis in the British population. The underlying pathophysiology of this link has not been established.[43]


HTLV-1: Definitive diagnosis of viral infection is with a range of serological tests; enzyme-linked immunosorbent assay (ELISA) is often employed as a screening test followed by a Western Blot as a confirmatory study to identify antibodies produced to the specific gag and env proteins of HTLV-1. Polymerase chain reaction (PCR) is advantageous in its ability to quantify proviral load and to differentiate between HTLV-1 and HTLV-2.[44]

ATLL: A significantly raised white blood count is usually present on presentation. Examination of peripheral blood cells and bone marrow is necessary for diagnosis and sub-classification of ATLL. Pathognomic morphological features of leukemic ATLL lymphocytes include dense chromatin with lobulated nuclei, which have the appearance of a cloverleaf and are sometimes referred to as “flower cells.”[45] Scattered blasts cells may be visible on blood film. Patchy infiltrates are present on examination of bone marrow. Histological assessment of lymphoid tissue is essential if the lymphomatous disease is queried. The architecture of diseased lymph nodes is significantly distorted with pleomorphic cells, which may appear similar to Reed-Sternberg cells, which can confuse the diagnosis with Hodgkin lymphoma.[46] Skin biopsy of cutaneous lesions may appear similar to changes seen in Mycosis Fungoides (cutaneous T cell lymphoma).

Several markers have been identified to be predictive of disease progression, including serum CD25, thymidine kinase, and neuron-specific enolase though these tests are rarely available outside of specialist centers.[47]

HAM/TSP: The World Health Organisation produced diagnostic criteria for HAM/TSP in 1988 comprising clinical, imaging, and laboratory tests, though, in clinical practice, newer techniques such as PCR quantification of HTLV-1 viral load in cerebrospinal fluid (CSF) is usually incorporated into a new diagnosis.[48] Magnetic resonance neuroimaging may identify discreet white matter lesions or spinal cord atrophy. CSF analysis classically identifies a mild leucocytosis, moderately raised protein, and detectable anti-HTLV-1 antibodies.

It is important to note that there is potential for significant confusion regarding the nomenclature of other human T cell lymphotropic viruses. HTLV-3 was the name initially given to the virus we now recognize as the Human Immunodeficiency Virus (HIV). HTLV-4 was previously used synonymously with HIV-2. This confusion has been demonstrated in clinical practice where more than 90% of diagnostic HTLV test requests were intended for HIV diagnosis.[49]

Treatment / Management

HTLV Vaccination: Currently, no vaccine is available; however, it has been hypothesized that various features of HTLV-1 render it amenable to vaccine development. These features include low antigenic variability of the virus and the observation that natural immunity does develop in humans. Some animal studies, including envelope antigens, have shown encouraging results.[12] The CCR4 receptor is a defined therapeutic target as it has been demonstrated to be integral to the viral transmission and host response.

Treatment for ATLL: Various combination chemotherapy regimens have been compared with highly active antiretroviral therapy (HAART) protocols in an effort to improve the morbidity and mortality of ATL patients. There is limited evidence that HAART (zidovudine-interferon alpha) may be beneficial in lymphomatous ATLL, whereas multi-agent chemotherapy is more beneficial in acute aggressive leukemic ATL. These strategies should be switched in non-responders.[33][23]

Intensive chemotherapy followed by allogenic hematopoietic stem-cell transplantation has shown promise in younger patients with aggressive disease; however, clinicians have expressed concerns that many patients are too old to receive this treatment as the median age at diagnosis is 68.[11] Long term maintenance combination chemotherapy with vincristine/methotrexate, prednisolone, etoposide/cyclophosphamide (OPEC/MPEC) has been shown to improve survival and quality of life in ATLL in older patients.[50]

Treatment for HAM/TSP: There are limited, robust treatment options for HAM/TSP though many have been trialed; the mainstay of management remains symptomatic. Corticosteroids have been widely used, and limited evidence suggests a moderate benefit in the rate of disease progression. Japanese centers have used mogamulizumab (a monoclonal antibody against CCR4) and reported decreased spasticity and improved motor function.[51] Anti-virals have been disappointing in their failure to modify disease progression.

Differential Diagnosis

ATLL: Differential diagnoses for ATLL center around other T cell malignancies and deciphering these can be challenging. ATLL can mimic cutaneous T cell lymphoma as cutaneous features, both macroscopically and histologically, are similar, and even immunohistochemical profiles in some cases are identical. Lymphomatous ATLL can produce lymphadenopathy morphologically similar to that of Hodgkin disease, and it may appear that Reed-Sternberg cells are present.[52] Finally, the examination of peripheral blood cells of asymptomatic patients with HTLV-1 infected patients may identify the “flower cells” characteristic of ATLL. Differentiating patients with the milder subtype of smoldering ATLL from these asymptomatic HTLV-1 patients without malignancy can be difficult, and PCR may be helpful to identify a malignant T cell clone associated with ATLL.

HAM/TSP: The main differential is multiple sclerosis, which can be difficult to exclude particularly a primary progressive form in a patient from an HTLV-1-endemic country. Identification of HTLV-1 within CSF is essential to securing a diagnosis of HAM/TSP. As described above, there are many neurological diseases that HTLV-1 appears to have the ability to induce including amyotrophic lateral sclerosis and conus medullaris syndrome; establishing a causative link in patients with concurrent neurological disease, and HTLV-1 infection is challenging.


Prognosis of HTLV-1 Infection: Acute infection is usually undetected and often occurs early in life through vertical transmission. The significant but variable time duration between acute infection and progression to a disease process implies that the presence of the virus in isolation is insufficient to induce pathogenesis. These likely additional factors are currently poorly understood therefore understanding of HTLV-1 prognosis is incomplete.

Prognosis of ATLL: ATLL is a fatal disease associated with very poor prognostic outcomes due to intrinsic resistance to chemotherapy and generalized immunosuppression.[23] Prognosis is dependent on sub-classification though the most common type (acute) is associated with the shortest survival. A US study of 195 ATLL patients analyzed over 16 years identified a median survival of 4 months for acute ATLL (n=80), 10 months for lymphomatous (n=96), and 72 months for chronic or smoldering ATLL (n=12). It is important to note that while prognosis appears comparably favorable in patients with chronic/smoldering ATLL this group only accounts for 6% of total study patients.[33] 

Prognosis of HAM/TSP: The disease course of HAM/TSP is extremely variable and there are limited identified predictors of disease progression through the viral load.[53] The majority of patients progress gradually but there are small subsets who progress rapidly to become wheelchair-bound in contrast to those who maintain almost complete neurological function and have only mild difficulty rising from a chair unaided.[38]


HTLV-1 is a common virus that is almost always asymptomatic during acute infection but is known to result in significant morbidity and mortality in up to 5% of affected individuals through conditions including ATLL and HAM/TSP. Clinical conditions usually develop years or decades after initial infection, and this often results in a delay of diagnosis, implication of HTLV-1 associated disease, and, therefore, appropriate management. ATLL and HAM/TSP are associated with significant morbidity, yet there remains uncertainty regarding the prediction of disease development, progression, and optimal management.

Deterrence and Patient Education

Patient awareness of HTLV-1 and knowledge of viral transmission and infection is evidenced to be lacking even in populations with a high prevalence of the virus.[54] Due to the nature of viral transmission, vulnerable groups, including sex workers and intravenous drug users are at higher risk of contracting HTLV-1; these are the same groups of people who may face major barriers to accessing healthcare. There is significant scope, therefore, for education initiatives surrounding the vertical transmission of HTLV-1 through breastfeeding, and horizontal transmission through sexual intercourse and needle-sharing.[55]

Enhancing Healthcare Team Outcomes

HTLV-1 is often acquired vertically during birth or infancy, and as described above, disease processes resulting from a viral infection may take many decades to manifest. These disease processes are far-reaching, and though usually manifest as neurological and hematological complications, other systems are well-known to be affected too, including dermatological, ophthalmological, and pulmonary. This necessitates a multi-disciplinary approach, not only for the broad range of potential diagnoses throughout all ages but also as the disease symptoms are the first indication of chronic HTLV-1 infection. Clinicians must employ a broad differential in considering HTLV-1 as a causative organism. Specialist laboratory techniques are undertaken to establish, quantify, and classify viral presence, and this may require communication and cooperation from multiple centers. 

As discussed above, further patient education is required in order to raise awareness of the virus and modes of transmission, particularly in endemic areas and in vulnerable patient groups. There remains a paucity of evidence relating to our understanding of co-factors involved in the progression from viral infection to disease processes such as ATLL and HAM/TSP. Further characterization of these factors may enable the prevention of pathology post-viral infection in the absence of vaccination/preventative strategies against HTLV-1 transmission.

Article Details

Article Author

Elizabeth S. Bryan

Article Editor:

Prasanna Tadi


7/4/2022 10:50:20 PM



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