HTLV-1

Human T-lymphotropic virus type 1 (HTLV-1) was the first human retrovirus to be discovered and the first retrovirus shown to cause a human cancer. It is a deltaretrovirus that establishes lifelong infection of CD4 T cells, and an estimated 5 to 10 million people carry it worldwide, almost certainly an underestimate given how rarely it is sought. The virus is biologically unusual: it spreads and persists chiefly by driving the clonal proliferation of the cells it has infected rather than by producing free virus. The great majority of carriers remain asymptomatic for life, but after a latency of decades a minority develop one of two very different diseases. Adult T-cell leukaemia/lymphoma is an aggressive malignancy of mature CD4 T cells, and HTLV-1-associated myelopathy, also called tropical spastic paraparesis (HAM/TSP), is a chronic inflammatory disease of the spinal cord. The virus shows striking geographic clustering, in southwestern Japan, the Caribbean, parts of South America, central and sub-Saharan Africa, the Middle East, Melanesia and central Australia. There is no cure for the infection and no licensed vaccine, so prevention depends on interrupting transmission, and the single most useful clinical measurement is the proviral load, the strongest predictor of who will progress to disease.

Discovery and historical significance

The disease was recognised before the virus. In the 1970s an unusual clustering of aggressive T-cell leukaemia was noticed in southwestern Japan, and Kiyoshi Takatsuki and colleagues defined adult T-cell leukaemia as a distinct entity, suspecting an infectious cause from its geographic concentration. In 1980 the virus itself, the first human retrovirus ever isolated, was recovered from a T-cell line, a discovery credited to Robert Gallo in the United States and, independently, to Yorio Hinuma in Japan; patients with adult T-cell leukaemia were soon shown to carry antibodies to it, linking the virus to the cancer. A few years later, in 1985 and 1986, two independent studies, by Antoine Gessain and colleagues in Martinique and Mitsuhiro Osame and colleagues in Japan, linked the same virus to a chronic myelopathy, establishing that this oncogenic retrovirus also caused a neurological disease.

Classification, structure, and genome

Classification

HTLV-1 is a retrovirus, in the genus Deltaretrovirus of the family Retroviridae. Its ICTV species is Primate T-lymphotropic virus 1, of which HTLV-1 is the human type, the species also containing the simian counterpart STLV-1. It belongs to a group of primate T-lymphotropic viruses, HTLV-1 to HTLV-4, that arose from repeated cross-species transmission between primates and humans over evolutionary time. HTLV-1 falls into several genetic subtypes that track ancient human migrations, a cosmopolitan subtype found worldwide and several African and Australo-Melanesian subtypes, though the sequence does not differ between people who stay asymptomatic and those who develop disease.

Virion structure

The virion is an enveloped particle about 100 nm across with the standard retroviral architecture. Its envelope glycoprotein is made as a precursor and cleaved into a surface protein, gp46, which binds the receptor, and a transmembrane protein, gp21. Within the envelope, the Gag proteins (the matrix protein p19 and the capsid protein p24) enclose the two genome copies together with the viral enzymes, reverse transcriptase, integrase and protease.

Genome organisation

The genome is a positive-sense RNA, carried in two copies, that is reverse-transcribed into a DNA provirus flanked by two long terminal repeats. As well as the structural and enzymatic genes (gag, pro, pol and env), it carries the regulatory genes tax and rex and several accessory genes (p12, p30 and p13) in a region called pX that fine-tune infectivity, latency and persistence. Its most distinctive feature is the HBZ gene: alone among the genes it is encoded on the opposite strand and transcribed from the 3’ long terminal repeat, an arrangement that turns out to be central to how the virus persists and causes cancer.

Replication cycle

HTLV-1 follows the retroviral pattern but with a decisive twist in how it propagates within the host.

HTLV-1 targets lymphocytes, principally the CD4 T cell. Entry uses three surface molecules in turn: the surface glycoprotein first binds heparan sulphate proteoglycans, which concentrate the virus at the cell surface, then the receptor neuropilin-1, a change that recruits the glucose transporter GLUT-1 to complete fusion. Once inside, reverse transcriptase copies the RNA genome into double-stranded DNA, and integrase inserts it as a provirus into the host chromosome, where most infected cells carry a single copy. Viral genes are then expressed in a regulated order: the first transcript encodes Tax and Rex; Tax amplifies transcription from the 5’ long terminal repeat in self-limiting bursts, and as Rex accumulates it shifts the balance towards the unspliced and singly spliced messages needed to make virion components. The HBZ gene is transcribed separately and continuously from the 3’ long terminal repeat.

The decisive departure from a conventional virus is what happens next. HTLV-1 makes very little free virus, and the cell-free particles it does release are poorly infectious. Instead it propagates in two ways: by infecting new cells through direct cell-to-cell contact at a structure called the virological synapse (a term first coined for this virus), where the infected cell polarises and delivers virus across an intercellular cleft to the target cell; and, far more importantly in established infection, by driving the infected T cell to divide, so that the provirus is copied by the host’s own machinery and passed to both daughter cells. This clonal, mitotic mode of spread is why reverse transcriptase and integrase inhibitors, which block new infection, do not lower the proviral load once infection is established, and why the host’s faithful DNA replication, rather than the error-prone reverse transcriptase, keeps the virus genetically stable.

Pathogenesis

HTLV-1 infects CD4 T cells, and the cells it eventually transforms have a regulatory-T-cell-like phenotype. Its pathogenesis turns on a division of labour between two viral proteins working from opposite ends of the provirus.

Protein	Strand / promoter	Expression	Role
Tax	Plus strand, 5’ long terminal repeat	Intermittent bursts; silenced in about half of leukaemias	Activates nuclear factor kappa B (NF-κB) and an interleukin-2 autocrine loop, drives proliferation and genomic instability; highly immunogenic, the main target of cytotoxic T cells
HBZ	Minus strand, 3’ long terminal repeat	Continuous, low level, in essentially all infected and leukaemic cells	Maintains the malignant clone, promotes a regulatory-T-cell phenotype, and helps keep the virus latent and hidden

Tax is the initiator: it switches on host proliferation and survival pathways, above all nuclear factor kappa B and an interleukin-2 autocrine loop but also the PI3K-Akt and CREB pathways, and it causes genomic instability. Expressed at high levels it can tip the cell into senescence, one reason it is produced only in intermittent bursts. But it is also the immune system’s main target, so infected cells survive by silencing the 5’ long terminal repeat (by deletion or methylation) to switch Tax off and escape cytotoxic T cells. The 3’ long terminal repeat stays active, so HBZ continues to be expressed; it is found in essentially every leukaemic cell, sustains the proliferation and survival of the clone, and drives the regulatory-T-cell phenotype. Tax initiates and HBZ maintains.

The proviral load, the proportion of blood cells carrying the provirus, is the central risk marker, because it reflects the number of distinct infected clones a person carries, which can exceed ten thousand; it is stable within an individual but varies more than a thousandfold between people, and it predicts the risk of both diseases. Adult T-cell leukaemia develops when one long-lived, proliferating clone accumulates additional driver mutations over decades, concentrated in the same T-cell-receptor and nuclear factor kappa B signalling pathways that Tax stimulates, in genes such as PLCG1, PRKCB and CARD11, with Tax-induced genomic instability and an impaired DNA-damage response speeding their acquisition; direct disruption of host genes by the integration site is not a major mechanism. The HBZ transcript adds to this, raising the proliferation factor E2F1 and, through BATF3, the MYC oncogene. HAM/TSP, by contrast, is immune-mediated: a high proviral load together with a vigorous but ineffective cytotoxic T-cell response leads infected CD4 cells and HTLV-1-specific CD8 cells to infiltrate the thoracic spinal cord, where the inflammatory cytokines they release, among them tumour necrosis factor and interferon gamma, cause demyelination and axonal damage, concentrated in the lateral corticospinal tracts, that produces the upper motor neuron signs; a strong cytotoxic response against HBZ, by contrast, is associated with a lower proviral load and a lower risk of disease.

Epidemiology

An estimated 5 to 10 million people are infected worldwide, a figure that is uncertain and probably an underestimate. Infection is not evenly spread but concentrated in endemic clusters: southwestern Japan, the Caribbean basin, parts of South America (Brazil has the largest absolute number of cases), central and sub-Saharan Africa, the Middle East, Melanesia, and central Australian Aboriginal communities, some of which have among the highest prevalences recorded, exceeding a tenth of adults, and where seroprevalence can rise above half in older women. Seroprevalence rises with age and is higher in women, because male-to-female sexual transmission is the more efficient direction. Transmission occurs by three main routes: breastfeeding, the principal route of mother-to-child transmission, with a risk of around 20 to 30 per cent that rises with prolonged breastfeeding and high maternal proviral load; sexual contact; and cellular blood products, organ transplantation and shared needles, transfusion being a highly efficient route while cell-free plasma carries little risk. The virus has travelled with human populations over tens of thousands of years, and its modern distribution still reflects ancient migration and the historical slave trade.

Natural history

Infection is lifelong, and the great majority of those infected never develop any related disease. Of the minority who do, the lifetime risk of adult T-cell leukaemia is about 5 per cent and of HAM/TSP about 2 per cent, although these vary with population, sex and, above all, the age at infection: the leukaemia is strongly linked to infection in infancy through breastfeeding, and rarely follows infection acquired in adulthood. Disease appears only after a long latency, with adult T-cell leukaemia typically diagnosed decades after infection, at a median age around fifty in the Caribbean and South America and later, nearer seventy, in Japan. The proviral load reaches a stable set point in each person that can differ more than a thousandfold between individuals, and it is this set point that best predicts who will progress. The absolute risks differ by population and sex, the leukaemia being relatively commoner in Japan and the myelopathy in Afro-Caribbean populations, and overall mortality among carriers is modestly raised, around one and a half times that of uninfected people, with excess deaths from the associated cancers, tuberculosis and Strongyloides infection.

Clinical presentations and complications

Adult T-cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma is an aggressive malignancy of mature CD4 T cells. The circulating tumour cells have characteristic indented, multilobulated nuclei, the flower cells, and a CD4-positive, CD25-positive, regulatory-T-cell-like phenotype; a raised soluble interleukin-2 receptor tracks the tumour burden, and eosinophilia is common. Frequent features are lymphadenopathy, hepatosplenomegaly, skin lesions (often with Pautrier microabscesses on biopsy), and a characteristic hypercalcaemia with lytic bone lesions, driven by osteoclast activation through tumour-derived RANKL and parathyroid-hormone-related protein. The disease causes profound cell-mediated immunodeficiency, so opportunistic infections, notably Strongyloides stercoralis hyperinfection, are common and worsen the outlook. It is divided into four clinical subtypes that determine prognosis and treatment.

Subtype	Character	Prognosis
Acute	Leukaemic, with lymphadenopathy, organomegaly, hypercalcaemia and skin lesions	Poor
Lymphomatous	Nodal lymphoma with few circulating cells	Poor
Chronic	Milder lymphocytosis; may transform to acute	Intermediate
Smouldering	Few circulating cells, skin or lung lesions	Least aggressive

HTLV-1-associated myelopathy / tropical spastic paraparesis

HAM/TSP is a slowly progressive inflammatory disease of the spinal cord, centred on the lateral corticospinal tracts of the thoracic cord. It presents with a spastic paraparesis: stiff, weak legs that on examination show the signs of upper motor neuron damage, hyperreflexia with clonus and bilateral extensor plantar responses (a positive Babinski sign), the clinical signature of corticospinal tract involvement that distinguishes the myelopathy from a peripheral neuropathy. The gait is stiff and unsteady, and bladder and bowel (sphincter) dysfunction appears early, often with back pain and sensory disturbance. It is two to three times commoner in women, and although it usually appears in mid-adult life after decades of infection, it can develop within months when infection is acquired through transfusion. Current understanding extends the picture into a wider HTLV-1 neurological complex, in which the virus also contributes to cognitive decline, peripheral neuropathy, inflammatory myopathy and autonomic disturbance, with the cognitive features tracking chronic inflammation rather than the proviral load, and the burden falling disproportionately and under-recognised on Latin America and the Caribbean.

Other associated diseases

HTLV-1 also causes uveitis, an intermediate uveitis that responds to corticosteroids but recurs; infective dermatitis of childhood, a severe relapsing eczema-like rash with bacterial superinfection that marks a high proviral load and predicts later leukaemia or myelopathy; inflammatory myositis and arthropathy; and chronic pulmonary disease such as bronchiectasis and alveolitis. Across all of these, the immunodeficiency it causes predisposes to Strongyloides hyperinfection and to tuberculosis.

Diagnosis

Diagnosis begins with serology: an enzyme immunoassay screens for antibody, and a positive result is confirmed by Western blot or line immunoassay, which also distinguishes HTLV-1 from the cross-reacting HTLV-2 using type-specific envelope antigens; a confirmatory Western blot requires reactivity to both Gag (p19 or p24) and Env (gp21 and gp46) antigens, and partial patterns are reported as indeterminate, which is common in parts of Africa. Because cell-free virus is scarce, diagnosis and monitoring rely on PCR of the integrated proviral DNA rather than on RNA, and quantitative PCR measures the proviral load. The diagnosis of adult T-cell leukaemia requires a proven T-cell malignancy in a person with HTLV-1 antibody, with demonstration of monoclonal integration of the provirus. HAM/TSP is diagnosed from the clinical myelopathy together with HTLV-1 antibody and provirus in the cerebrospinal fluid, which typically shows a mild lymphocytic pleocytosis, raised protein and HTLV-1-specific oligoclonal bands, after excluding other causes of a progressive myelopathy such as cord compression, multiple sclerosis and vitamin B12 deficiency.

Management

There is no cure for the infection, and treatment is directed at the disease. Adult T-cell leukaemia carries a poor prognosis. Aggressive (acute and lymphomatous) disease is treated with intensive combination chemotherapy, such as the VCAP-AMP-VECP regimen used in Japan, though responses are often short-lived and median survival is measured in months; the leukaemic subtypes may be treated with zidovudine combined with interferon alfa, which acts on the clone rather than on viral replication; mogamulizumab, an antibody against the CCR4 receptor expressed on the tumour cells, kills them by enhanced antibody-dependent cytotoxicity; and allogeneic stem-cell transplantation offers the only realistic chance of cure in selected patients. HAM/TSP has no cure and is managed with corticosteroids for the inflammatory component, high-dose pulsed methylprednisolone for flares and low-dose maintenance to slow progression, together with symptomatic treatment of spasticity and bladder dysfunction and physiotherapy; mogamulizumab lowers the proviral load in trials, and epigenetic agents such as valproic acid are under investigation. Importantly, antiretroviral reverse transcriptase inhibitors do not help established disease, because it is maintained by clonal proliferation rather than ongoing viral replication, and they have a role only in post-exposure prophylaxis.

Prevention and public health

Vaccination

There is no licensed vaccine. Unlike HIV, a preventive vaccine is thought to be achievable, since antibody and envelope-based vaccines block transmission in animal models, but no candidate has yet been tested for efficacy in people.

Surveillance and notification

The World Health Organization has identified HTLV-1 as a neglected infection and is developing its first global guidance on testing, prevention and surveillance, with better burden estimation and affordable testing as priorities. The practical public-health measures already in use interrupt the main transmission routes: screening blood donations and organ donors, which almost eliminates transfusion transmission; antenatal screening with avoidance of breastfeeding by infected mothers, or shortened breastfeeding where formula is not feasible; and condom use and safe-injection or needle-exchange programmes.

South African context

HTLV-1 circulates in parts of Africa, with recognised endemic foci in central and western regions, and it is present in South Africa, although systematic local prevalence data are limited. The practical points for South African practice are that blood services screen donations for HTLV-1, because transfusion is a highly efficient route of transmission, and that the virus should be considered in patients from higher-prevalence communities, particularly given the local importance of the Strongyloides hyperinfection and tuberculosis that its immunodeficiency predisposes to.

References and recommended reading

• Bangham CRM, Matsuoka M. Human T-Lymphotropic Viruses (HTLV-1 and HTLV-2). In: Fields Virology, 7th edition, Volume 3, Chapter 16. Wolters Kluwer; 2023. The primary reference for the virology, the Tax and HBZ biology, clonal persistence and oncogenesis.
• Bruhn RL, Mahieux R, Murphy EL. Human Lymphotropic Viruses: HTLV-1 and HTLV-2. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The clinical account of the leukaemia subtypes, the myelopathy and the diagnostic workflow.
• Araujo AQC, Silva MTT. HTLV-1-associated myelopathy / tropical spastic paraparesis. Lancet Regional Health - Americas 2026;55:101347. The current view of HAM/TSP and the wider HTLV-1 neurological complex.
• World Health Organization. Human T-lymphotropic virus type 1 (HTLV-1) fact sheet; 2025. The source for the global epidemiology, transmission and the lifetime risks of disease.