Because GLUT-1 and HSPG are reported to be expressed on the surface of many cell types, it has been found that not only CD4 + T cells but also CD8 + T cells and other cell types can be infected by HTLV-1 however, CD4 + T cells constitute the major population of HTLV-1-infected cells in vivo with frequent clonal expansion ( 15, 20, 21, 22, 23). Additionally, neuropilin-1, a member of the immune synapse, forms ternary complexes with GLUT-1 and Env, indicating that neuropilin-1 is also involved in Env-mediated cell fusion and viral infection ( 19). This suggests that Tax is mainly involved in virus replication and transmission as well as in the early stages of tumorigenesis.Īlthough a number of cell surface molecules have been reported to play a role in HTLV-1 envelope (Env)-mediated syncytium formation ( 15), glucose transporter-1 (GLUT-1) and heparan sulfate proteoglycan (HSPG) appear to be of primary importance in HTLV-1 infection ( 16, 17, 18). Thus, ATL cells usually do not express the tax gene and are considered to be independent of the growth-promoting effects of Tax ( 3, 4). However, ATL develops only after a long period of latency, usually after several decades, and during this period, tumor progression occurs through the accumulation of multiple genetic alterations ( 1, 3, 4). The potent viral transactivator Tax is known to activate both the HTLV-1 long terminal repeat and the promoters of various cellular genes, leading to strong promotion of cell proliferation and activation ( 7). In vitro, HTLV-1 is capable of transforming CD4 + T cells into continuously growing T cell lines ( 2, 3). Therefore, HTLV-1 transmission between individuals occurs by the transfer of infected lymphocytes through breast milk, semen, or blood ( 4, 6). HTLV-1-infected lymphocytes produce very few infectious cell-free virions, and the virus is mainly transmitted via cell-cell contacts ( 2, 4, 5). Although the majority of infected individuals remain lifelong asymptomatic carriers, HTLV-1 is also etiologically associated with adult T cell leukemia (ATL) and a range of inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis, which is a chronic disease of the CNS ( 1, 2, 3). Human T cell leukemia virus type 1 (HTLV-1) 3is an exogenous retrovirus that infects 10∼20 million people worldwide ( 1, 2, 3, 4). Thus, HTLV-1-infected T cells produce CCL22 through Tax and selectively interact with CCR4 +CD4 + T cells, resulting in preferential transmission of HTLV-1 to CCR4 +CD4 + T cells. Finally, anti-CCL22 Ab treatment also blocked HTLV-1 transmission to primary CD4 + T cells in coculture experiments with HTLV-1 producer cells. Interestingly, CCR4 was redistributed to the contact region, and in some cases, this was accompanied by a polarized microtubule-organizing center, which is an indicator of virological synapse formation, in the infected T cells. This adhesion was blocked by the CCR4 antagonist or pertussis toxin. In coculture experiments, primary CCR4 +CD4 + T cells significantly adhered to Tax-expressing cells. This was blocked by pretreating the supernatants with anti-CCL22 Ab or PBMCs with a synthetic CCR4 antagonist. In chemotaxis assays, the culture supernatants of HTLV-1-infected T cells selectively attracted CCR4 +CD4 + T cells in PBMCs. These findings indicate that CCL22 is a cellular target gene of Tax. Additionally, tax gene knockdown by small interference RNA reduced CCL22 expression in the infected T cells. Transient Tax expression in an HTLV-1-negative T cell line activated the CCL22 promoter and induced CCL22. In terms of gene expression and protein secretion, we found a strong correlation between HTLV-1 Tax oncoprotein and CCL22, a CCR4 ligand, in HTLV-1-infected T cells. Because HTLV-1 transmission depends on close cell-cell contacts, HTLV-1-infected T cells may preferentially interact with CCR4 +CD4 + T cells for efficient viral transmission. Adult T cell leukemia is a mature CD4 + T cell malignancy which predominantly expresses CCR4 and is etiologically associated with human T cell leukemia virus type 1 (HTLV-1).
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