The first known pathogenic human retrovirus was isolated in 1980 from the lymphocytes of a patient with cutaneous T-cell lymphoma (CTCL) by Poiesz and coworkers.1 Independently, Miyoshi and co-workers later isolated an identical retrovirus from a Japanese leukemia patient.1 The name human T-cell leukemia virus type 1 (HTLV-1) is used now for all isolates previously called adult T-cell leukemia virus in Japan and HTLV in the United States.

An estimated 10–20 million individuals are infected by HTLV-1 worldwide,2–4 with an endemic pattern in Southern Japan, the Caribbean islands, and some countries in equatorial Africa. In some of these locations, most notably the Japanese islands Shikoku, Kyushu, and Okinawa, the seroprevalence reaches 36%.2–4 Small clusters of HTLV-1/HTLV-2 seropositive populations have been reported in restricted areas in South America, among Australian aborigines, and in the Middle East.2–4 In the United States and Europe, the incidence of HTLV-1 infection is below 0.1%, and clusters are found predominately among immigrants from endemic areas, especially those from the West Indies and Africa.2–4

Sexual intercourse is the main mode of horizontal transmission of HTLV-1.2–4 In vertical transmission, breast-feeding plays a more important role than perinatal or intrauterine transmission.2–4 Parenteral transmission of HTLV-1 is also possible, and approximately one-half of patients who received transfusions from an HTLV-1-infected donor seroconvert,2–4 however, the transmission risk by blood transfusion in low prevalence countries is minimal.4,5 Transfusion-mediated HTLV-1 infection in Japan has been virtually eliminated by mass screening of donated blood. In contrast to blood transfusions, cell-free, fresh, frozen plasma appears not to be infectious.5 Parenteral transmission via needle sharing very likely accounts for clusters of HTLV-1/HTLV-2 seropositivity in intravenous drug users in certain areas of the United States and Europe.6

HTLV-1 together with HTLV-2, a virus that has not yet been clearly associated with any human disease, and bovine leukemia virus form their own genus within family Retroviridae.2 Many strains of HTLV-1 have been isolated in different areas of the world, including the United States, the Caribbean islands, Africa, and Japan.3 The overall nucleic acid sequence variation among different HTLV-1 strains does not exceed 7%. By comparison, the nucleotide sequence conservation between HTLV-1 and HTLV-2 is only approximately 55%. In addition to genes coding for viral structural proteins, both the HTLV-1 and HTLV-2 genomes contain an extra sequence of approximately 1.6 kilobases between the env and the 3′ LTR, which contains several regulatory genes. These include the transregulatory proteins Tax (transactivator in the region x) and Rex (regulator in the region x), whose functions have been elucidated, but the function of the other proteins of the pX region—p21Rex, p12I, p13II, and p30II—still awaits full clarification.2,7–9

Infection of human, monkey, and rabbit T lymphocytes by HTLV-1 in vitro leads to their continuous growth in tissue culture and the development of cell lines with growth characteristics of transformed cells. In infected patients, HTLV-1 is present mainly in CD4+ T cells.10 The steps leading from virus infection to the development of the different HTLV-1-associated diseases are still only partly understood. Only a small percentage of patients infected with HTLV-1 ultimately develop adult T-cell leukemia (ATL), and the time from infection to the appearance of leukemia is usually several decades.2,4

Tax, the viral transactivator, is necessary for the transformation of T cells. It interferes with at least two inhibitors of cell cycle progression, including the tumor suppressor protein p16ink and p53.2.8 In the transformed state, HTLV-1-infected T cells proliferate in the absence of exogenous growth factors. This event correlates with both the constitutive activation of the Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway8 and the constitutive activation of the cyclin E/cyclin-dependent kinase 2 complex. The in vitro model of T-cell transformation appears to mirror the event that leads to leukemogenesis. In most cases of ATL, genetic mutation or deletion of p53 or p16ink occurs,8 and the leukemic cells of 70% of patients display constitutive activation of the Jak3 and STAT proteins.8 An antisense transcript of HTLV-1 from the 3′ long terminal repeat and called HTLV-1 bZIP factor (HBZ) has been identified, its expression was documented HTLV-1-infected cells as well as in all ATL cases studied and its expression is correlated with proviral load.11 HBZ mRNA promotes proliferation of ATL cells and is thought to play a critical role in leukemogenesis.

Although HTLV-2 has been less well studied than HTLV-1, most of the properties described for the latter, including the transformation of T cells in vitro and the presence and importance of transregulatory genes, are also true for the former.2 As noted above, no disease has been associated with HTLV-2 infection, to date.

Adult T-Cell Leukemia/Lymphoma

Uchiyama and co-workers first described ATL in 1977 as a distinct malignancy of mature T cells occurring primarily in patients born in Southwestern Japan.1–4,12 At the beginning of the 1980s, HTLV-1 was linked to ATL by virus isolation from leukemic cells, by the demonstration of oligoclonal or monoclonal integrated HTLV-1 provirus in leukemic cells, and by extensive seroepidemiologic studies.1,2,4,8 Besides Japan, the West Indies are a major region where HTLV-1 infection and ATL are endemic.2–4

Although the presence of HTLV-1 is a prerequisite for ATL development, infection with this virus does not necessarily lead to the occurrence of leukemia. More than 90% of infected individuals remain asymptomatic carriers.2,12 The annual incidence rate of ATL among HTLV-1 carriers older than 40 years is approximately 0.6–1.7 in 1000.13 The cumulative incidence rate of ATL in HTLV-1 carriers approximates 2–5%. The latent period from infection to outbreak of leukemia is 20 years or longer, as concluded from studies in migrants.14 Interestingly, the average age of onset of ATL differs in patients in Japan (56 years) and in the Caribbean (43 years).15

According to the World Health Organization’s lymphoma classification, ATL is a peripheral T-cell lymphoma. Based on the clinical course and laboratory parameters, ATL is classified into four subtypes—(1) smoldering (5% of cases), (2) chronic (15%), (3) lymphoma type (20%), and (4) acute or prototypic ATL (60%)—for which diagnostic criteria have been formulated (Box 197-1).16,17