Human T cell lymphotropic virus type I and cutaneous T cell leukemia/lymphoma [published erratum appears in J Exp Med 1995 Jan 1;181(1):441]

H uman T cell lymphotropic virus type I (HTLV-I) is a mammalian retrovirus that has a tropism for mature T lymphocytes and an association with rare clinical disorders (1, 2). HTLV-I infection is endemic in a number of geographic regions which include parts of Japan, the Caribbean, South America, and Africa. Despite very high rates of infection in endemic areas where as many as 30% of the population may be infected, relatively few infected individuals develop disease, and it has been estimated that the lifetime risk of developing a HTLV-I-related clinical disorder is less than 5% (1, 3, 4). The vast majority of infected individuals remain as asymptomatic carriers, and serve as a source of further transmission of the virus. Transmission occurs by three major routes: vertically from mother to child, which occurs primarily through breast-feeding; heterosexual and homosexual transmission; and via contaminated blood products, which may occur after blood transfusion or by intravenous drug abuse (1, 2). Outside of established endemic areas, the rates of infection are unknown, but appear to be comparatively low. In the United States, studies on randomly chosen blood donors have indicated that this may be in the region of 0.0016% (2), and similar rates probably exist in Europe. In nonendemic areas, the modes of transmission are presumably the same as in endemic regions. However, it seems likely that blood transfusion is very important in those countries where the blood supply is not routinely screened for HTLV-I infection. In endemic areas, HTLV-I infection is associated with a number of diverse clinical disorders. These include adult T cell leukemia (ATL), a malignancy of CD4 + lymphocytes, and a form of cutaneous T cell leukemia/lymphoma (CTCL) (5, 6), a chronic encephalomyelopathy known both as tropical spastic paraparesis and HTLV-I-associated myelopathy (TSP/HAM) (7, 8), and a characteristic uveitis, HTLV-Iassociated uveitis (HUV) (9, 10). In addition, there have been suggestions that HTLV-I may be associated with other inflammatory processes including T cell alveolitis (11), polymyositis (12), arthritis (13, 14), infective dermatitis (15), and Sjogrens syndrome (16). However, it is unclear if the association of infection with the latter group of disorders is merely coincidental, and further studies will be required to definitely establish a role of the virus in their pathogenesis. Very recently, there have been suggestions that in certain nonendemic areas, HTLV-I may be associated with a number of CTCLs other than ATL. This view is strongly supported in a publication by Manca et al. (17) in this issue of The Journal of Experimental Medicine where the PCR was employed to detect HTLV-I infection in patients with mycosis fungoides. In this commentary, the evidence for a role of HTLV-I in the etiology of CTCLs will be reviewed and summarized. ATL, which was first recognized as a unique dinical disorder in Japan in the 1970s (18), is a malignancy of mature CD4 § T lymphocytes with characteristic cutaneous involvement. The disorder has been classified into four types: the so-called acute, chronic, smouldering, and lymphoma types (10). The acute form of the disease is an extremely aggressive disorder characterized by a high-grade leukemia, skin lesions, and widespread systemic involvement resulting from infiltration of leukemic cells in liver, spleen, lungs, lymph nodes, and bone marrow. In addition, lytic bone lesions with an associated hypercalcemia commonly occurs. Cutaneous involvement is characterized by infiltration of leukemic cells primarily into the dermis and subcutaneous tissues. While epidermal infiltration also occurs, this is comparatively rare. The HTLV-I provirus is monoclonally integrated in the leukemic cells, and the majority of patients have high levels of antibody to HTLV-I. Leukemic cells characteristically display activation markers including CD25 (IL-2R) and HLA-DR (1, 10). Chronic ATL is a much less aggressive form of the disease. Patients generally have skin involvement, but systemic involvement as occurs in acute ATL is rare. While many patients.display a lymphocytosis, only small numbers of abnormal cells are present in peripheral blood (10). Smouldering ATL is an even more indolent process. Characteristically, this is of long duration and presents as cutaneous disease with few, if any, of the other features of acute ATL. Lymphocytosis is generally not evident and there are few or no abnormal lymphocytes in peripheral blood. Both chronic and smouldering ATL are considered to be pre-leukemic states with overt acute disease developing after many years of latency (10, 19). Lymphoma type ATL is characterized by prominent lymphadenopathy due to the presence of HTLV-I-transformed T lymphocytes in lymphatic tissues, but the leukemic component observed in acute ATL is absent. The observation that chronic and smouldering ATL may be pre-leukemic conditions has led to the hypothesis that the development of acute ATL is a progressive process beginning with the infected asymptomatic carrier through an intermediate state of the chronic/smouldering forms of the disease and eventually to overt ATL (10, 19). During these stages the integration pattern of the provirus changes from polyclonal in the carrier and intermediate states to monoclonal, which is characteristic of the transformed leukemic cells. The mechanisms involved in cellular transformation remain poorly understood. HTLV-I does not contain an oncogene as exists