Effects of nucleoside-based antiretroviral chemotherapy on human T cell leukaemia/lymphotropic virus type 1 (HTLV-1) infection in vitro

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Abstract
Human T cell leukaemia/lymphotropic virus type 1 (HTLV-1) infection is nowadays considered a global epidemic since 10–20 million individuals are estimated to be carriers of the virus and the risk of developing disease in endemic areas has been evaluated as 5% in asymptomatic patients. HTLV-1 is endemic in south-western Japan, in the Caribbean basin, where 3–4% of the population is seropositive for the virus, in North and South America and in some areas of Africa. The main modalities of transmission are: (i) perinatally, mainly breast feeding; (ii) parenterally, blood transfusion and sharing of needles and syringes infected with contaminated blood in drug abusers; and (iii) sexual contacts.1 HTLV-1 is associated with a variety of clinical diseases. Initially it was linked to a chronic adult T cell leukaemia/lymphoma (ATLL), and, later, to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), both found in endemic areas of Japan and of Central and South America. ATLL is usually classified in five stages: asymptomatic, pre-leukaemic, chronic/smouldering, lymphoma and acute. Chronic/smouldering ATLL displays mild symptoms, whereas acute ATLL shows a rapid progression of the disease. Chronic ATLL presents a high number of leukaemic cells in the periphery whereas acute ATLL is characterized by lymphoadenopathy, hypercalcaemia and hepatosplenomegaly. Patients with HAM/TSP present spasticity of the lower extremities, weakness of the lower muscles and dysfunction of the urinary bladder.2,3 Recently, HTLV-1 has also been associated with polymyositis, arthropathy and uveitis.1 Anti-cancer chemotherapy has always been the only treatment for ATLL.4 In addition, combinations of classical anti-cancer chemotherapy with interferons (IFNs) and with monoclonal antibodies against the interleukin-2 (IL-2) receptor have been found to induce a limited benefit in 50% of ATLL patients. However, recently it has been reported that therapy with nucleoside-based antiretroviral agents, either alone or in combination with IFN, has the ability to control the proliferation of HTLV-1-infected cells and to assure a partial response in HTLV-1-infected patients.5–8 Nevertheless, the use of nucleoside analogues in HTLV-1 therapy is still subjected to criticism because HTLV-1 infection in vivo is accompanied by limited viraemia. Furthermore, several in vitro studies have shown that the use of β-IFN or combinations of cytotoxic and antiproliferative drugs provides protection against virus transmission to cord blood CD4 lymphocytes9 or cell cycle arrest and apoptosis in HTLV-1 transformed cells,10 respectively. Conversely, not enough in vitro data were available to encourage the use of nucleoside-based antiretroviral therapy in HTLV-1-associated diseases. Thus, we focused our attention on this aspect. A possible, disease-related method to investigate the potentialities of nucleoside-analogues in HTLV-1 infection is to analyse the effects of the drugs on virus transmission using reproducible in vitro models.

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