Chapter 197. Human T-Lymphotropic Viruses

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

Acute, prototypic ATL is a fatal malignancy of adult onset with a clinical presentation that appears to be identical in all endemic areas.54,12,16,17 It is characterized by the variable combination of multiorgan involvement, including hepatosplenomegaly, systemic lymphadenopathy, central nervous system involvement, and skin lesions, with the massive presence of multilobated leukemic cells in the peripheral blood (Fig. 197-1A). The presence of leukemic infiltrates in different organs determines the clinical presentation and the morbidity: central nervous system involvement may alter the mental status of the patient; lymphoma within the liver may lead to abnormalities in liver function test results and jaundice; and lung involvement may lead to tachypnea, cyanosis, and dyspnea.

A striking feature in a high percentage of patients with acute ATL is refractory hypercalcemia, which may be the first sign of the disease and indicates an aggressive course.4,12,16–18 Patients may have weakness, lethargy, polyuria, and polydipsia. Lytic bone lesions resembling those of multiple myeloma are often present at the time of diagnosis, and levels of alkaline phosphatase may be elevated.4,18 Parathyroid hormone levels and 1,25-dihydroxyvitamin D levels are normal in ATL patients with hypercalcemia. Factors produced by leukemic cells themselves have been suggested to account for the hypercalcemia and bone resorption in ATL patients.

Lymphoma-type ATL also shows severe organ involvement and high serum levels of lactic acid dehydrogenase and may be associated with hypercalcemia. Unlike in acute ATL less than 1% leukemic cells are present in the peripheral blood. Both lymphoma-type and acute ATL have a poor prognosis, with a projected 4-year survival of no more than 5%.4,12,17

Smoldering and chronic ATL have more protracted courses; however, they may convert into acute ATL.4,12,16,17

The skin involvement in ATL varies considerably among patients and is present to a variable degree in all forms of ATL.4,12,19–21 Skin lesions may appear as uncharacteristic erythematous patches, as papules and nodular tumors (Fig. 197-2), and as erythroderma. Nonspecific skin lesions may precede the onset of acute ATL by up to two decades.21 Specific skin infiltrates may occur as the first manifestations of ATL, and monoclonality of skin-infiltrating cells may be evident by the criteria of both T-cell receptor rearrangement and integration of HTLV-1 DNA. This occurs at a time when circulating T cells of these patients still appear unaffected.20 To designate this latter situation, the term cutaneous-type ATL has been proposed.20 However, it is questionable whether this form represents an independent type of ATL or should be included in the smoldering form. Alternatively, it may reflect very early detection of prototypic or chronic ATL as a result of improved diagnostic methods.

Diagnosis and Differential Diagnosis of Adult T-Cell Leukemia

Not only does prototypic ATL show a characteristic clinical course but examination of the leukemic cells yields a characteristic picture: numerous multilobated cells called ATL cells or flower cells (see Fig. 197-1A) are present in peripheral blood and can usually be readily distinguished from cells of other T-cell leukemias by light microscopy, although sometimes occasional cells indistinguishable from Sézary cells may be present.4,12,16,17 In smoldering-type ATL and chronic-type ATL, multilobated cells are less frequent, and in lymphoma-type ATL they may comprise fewer than 1% of lymphocytes (see Box 197-1). Monoclonal integration of HTLV-1 DNA4,12,16,17 in leukemic cells as well as in affected organs is a diagnostic criterion. Immunophenotyping shows that leukemic cells display predominantly a mature CD2+/CD3+/CD4+/CD8−/CD25+ phenotype.4,12,16,17 Although most of these T-cell markers can be found in other T-cell malignancies, the strong expression of the interleukin 2 receptor α chain (CD25) can be regarded as a distinguishing marker differentiating ATL and Sézary syndrome.12,16,17,22

The histopathologic features seen in affected organs and lymph nodes are more variable than the signs in peripheral blood, and ATL is associated with lymphomas of several histologic subtypes. Differentiation of ATL from other peripheral T-cell lymphomas, especially HTLV-1-positive and HTLV-1-negative cases, on morphologic grounds is not possible. No specific pathologic finding distinguishes ATL from other forms of non-Hodgkin lymphoma. Difficulties can also be encountered in differentiating the skin manifestations of ATL from mycosis fungoides (MF) and Sézary syndrome, because focal epidermal infiltration by T cells or Pautrier's microabscesses (see Fig. 197-1B) can be present in skin lesions of ATL.21,23,24 Indeed, the diseases of patients from whom the original US HTLV-1 isolates were obtained were originally classified as Sézary syndrome and CTCL.1 Four diagnostic criteria have been put forward that must be fulfilled to unequivocally establish the diagnosis of HTLV-1-associated ATL4,12,16,17: (1) a histologically or cytologically proven lymphoid malignancy with T-cell surface antigens must be present; (2) abnormal T lymphocytes must be detected in peripheral blood, except in the lymphoma type; (3) anti-HTLV-1 serum antibodies must be present; and (4) the clonality of HTLV-1 proviral DNA must be demonstrated.

The fact that the first HTLV-1 isolates were obtained from patients misclassified as having MF and Sézary syndrome, together with the earlier reports regarding the presence of retroviral particles in the skin and lymph nodes of patients with these diseases, has prompted an intensive search for HTLV-1 in CTCL. Although several reports claimed that HTLV-1 DNA sequences were detectable in tumor tissue and in cell lines derived from MF patients, an overwhelming majority of investigators, studying patients from the same geographic regions with comparable methods, were unable to find HTLV-1 DNA in CTCL samples.25 It is now well accepted by most that HTLV-1 is not involved in the pathogenesis of CTCL (see Chapter 145).

Prognosis and Treatment of Adult T-Cell Leukemia

The prognosis of ATL depends largely on the subtype. In the most extensive study on the course of ATL to date, 818 Japanese patients newly diagnosed with the disease were studied for a median follow-up time of 13.3 months.12,15 Median survival time was 6.2 months for those with the acute type, 10.2 months for those with the lymphoma type, and 24.3 months for those with the chronic type. Projected 2- and 4-year survival rates were, respectively, 16.7% and 5.0% for the acute type, 21.3% and 5.7% for the lymphoma type, 52.4% and 26.9% for chronic type, and 77.7% and 62.8% for the smoldering type. The presence of hypercalcemia, high levels of lactic acid dehydrogenase, and an excessively high white blood cell count are prognostic factors4,12,15–17,26 associated with poor survival.

Treatment of ATL remains disappointing. Combination cytotoxic therapy used to treat non-Hodgkin lymphoma has little effect on prototypic ATL and ATL lymphoma. Although complete remission can be achieved in up to 40% of patients with different combinations of conventional chemotherapy, most of the patients experience relapse within weeks or months, and the 4-year overall survival rate is below 10%.4,12,15–17,26 Frequent complications of treatment include septicemia and opportunistic infections, which result from chemotherapeutic intensification of the immune suppression already present in ATL patients. Besides conventional chemotherapy, the combination of interferon-α and zidovudine, a nucleoside analog used against human immunodeficiency virus type 1 (see Chapter 231), has shown some effect in the treatment of acute and lymphoma-type ATL.15–17,26 Allogeneic hematopoietic stem-cell transplantation that has been used in several clinical trials ATL,26 holds some promise for the future. Other therapeutic approaches,17,26 including the use of monoclonal antibodies against surface molecules of leukemic cells, arsenic trioxide, proteasome inhibitors, and angiogenesis inhibitors, have been under study; however, to date no breakthrough has been reported.

The course of smoldering and chronic ATL is less dramatic, internal organ involvement and hypercalcemia are observed less frequently than in ATL lymphoma and acute ATL, and the prognosis is better.4,12,15–17,26 Because chemotherapy-associated immunosuppression increases the immunosuppression caused by the disease itself, early chemotherapy may be more harmful than beneficial for patients with smoldering and chronic ATL. Therefore, these patients should not be treated with chemotherapy unless they enter a more aggressive phase of their disease. The combination of zidovudine and interferon-α has been suggested as a possible treatment for these clinical variants.

Nonmalignant Sequelae of Human T-Lymphotropic Virus 1 Infection

Neurologic Disease

HTLV-1 infection is associated with chronic progressive myelopathy, which is referred to as tropical spastic paraparesis (TSP) in the Caribbean and HTLV-1-associated myelopathy (HAM) in Japan.27 Patients with TSP/HAM are generally younger at disease onset than ATL patients. The latent period from infection to development of clinical neurologic symptoms has been described to be very short in individual cases. The lifetime risk for developing TSP/HAM has been estimated at 1%.28 In contrast to ATL, which is associated with HTLV-1 infection very early in life, TSP/HAM frequently occurs in patients who became infected only in adolescence. In particular, the acquisition of HTLV-1 by blood transfusion has been reported to play an important role in the development of TSP/HAM.

Infective Dermatitis

Infective dermatitis (Fig. 197-3) is a severe, chronic, relapsing eczema in Jamaican children29 associated with infection by Staphylococcus aureus and β-hemolytic Streptococci.29 An association between infective dermatitis and HTLV-1 infection has been reported. Bacterial infection in infective dermatitis is difficult to control, and although it responds to antibiotic treatment, prolonged therapy is necessary and relapses are common after discontinuation. The characteristic clinical picture, the recalcitrant course, and HTLV-1 seropositivity sets infective dermatitis apart from other forms of recurrent eczema, including atopic eczema.29 Immunosuppression observed in HTLV-1 carriers, as well as in ATL patients,30 may play a role in the pathogenesis of infective dermatitis. Although HTLV-1-infected individuals are overrepresented among patients hospitalized for infectious diseases in Japan, infective dermatitis has rarely been reported in regions outside the Caribbean. Regional, cultural, or genetic factors may play an additive role in the occurrence of infective dermatitis. Evidence that infective dermatitis in childhood might be associated with subsequent development of ATL comes from studies of HTLV-1 infection and infective dermatitis in Jamaica.31,32 In addition to infective dermatitis, several other infectious and noninfectious skin disorders are frequently observed in HTLV-1-infected individuals.33

Other Disorders

In addition to the diseases described in the previous sections, certain types of uveitis, polymyositis, chronic inflammatory arthropathy, and peripheral neuropathy have been suggested to be associated with HTLV-1 infection.4 However, future epidemiologic and virologic studies will be necessary to establish the causative role of the virus in the pathogenesis of these diseases.