Human T-cell Lymphotropic Virus type 1 (HTLV-1) is a human retrovirus that infects at least 5–10 million people worldwide, and is the etiological agent of a lymphoproliferative malignancy; Adult T-cell Leukemia/Lymphoma (ATLL); and a chronic neuromyelopathy, HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), as well as other inflammatory diseases such as infective dermatitis and uveitis. Besides sexual intercourse and intravenous transmission, HTLV-1 can also be transmitted from infected mother to child during prolonged breastfeeding. Some characteristics that are linked to mother-to-child transmission (MTCT) of HTLV-1, such as the role of proviral load, antibody titer of the infected mother, and duration of breastfeeding, have been elucidated; however, most of the mechanisms underlying HTLV-1 transmission during breast feeding remain largely unknown, such as the sites of infection and cellular targets as well as the role of milk factors. The present review focuses on the latest findings and current opinions and perspectives on MTCT of HTLV-1.

The human T-lymphotropic virus type 1 (HTLV-1) is efficiently transmitted through cellular contacts. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied in vitro, those facilitating the encounter between infected and target cells remain unknown. In this study, we demonstrate that HTLV-1-infected CD4 T cells secrete a potent chemoattractant, leukotriene B4 (LTB4). LTB4 secretion is dependent on Tax-induced transactivation of the pla2g4c gene, which encodes the cytosolic phospholipase A2 gamma. Inhibition of LTB4 secretion or LTB4 receptor knockdown on target cells reduces T-cell recruitment, cellular contact formation and virus propagation in vitro. Finally, blocking the synthesis of LTB4 in a humanized mouse model of HTLV-1 infection significantly reduces proviral load. This results from a decrease in the number of infected clones while their expansion is not impaired. This study shows the critical role of LTB4 secretion in HTLV-1 transmission both in vitro and in vivo.

Human T-lymphotropic virus type 1 (HTLV-1

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Isolated HTLV-1 viral particles are poorly infectious both in vivo and in vitro. In contrast, the virus is efficiently transmitted through cell-to-cell contact. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied, the mechanisms facilitating the encounter between an infected cell and a target cell remain unknown. We postulated that the infected cells could behave as a source of chemoattractant, thus recruiting target cells. In 2012, Trindade et al. showed that PBMCs from HTLV-1 infected individuals (HTLV-1 asymptomatic carrier and HAM/TSP patients) could secrete higher levels of leukotriene B4 (LTB4), a potent chemoattractant, than cells from healthy donors. We proposed that, although T cells purportedly secrete no LTB4, LTB4 could be secreted by HTLV-1 infected lymphocytes and facilitate cell-to-cell contacts and viral transmission. We showed by ELISA that HTLV-1 infected lymphocytes (both primary CD4+ T cells and chronically infected cell lines) secrete LTB4. By cell transduction with lentiviral vectors encoding Tax, we suggest that HTLV-1 induced LTB4 secretion is a consequence of Tax-induced cytosolic phospholipase A2 (cPLA2) over expression. Blocking LTB4 secretion (with diverse specific inhibitors of the leukotriene pathway) prevented the recruitment of potential target cells, as well as the formation of cell-to-cell contacts. In conclusion, HTLV-1 diverts the leukotriene pathway and LTB4-mediated chemotaxis facilitates viral propagation.

Isolated HTLV-1 viral particles are poorly infectious both in vivo and in vitro. In contrast, the virus is efficiently transmitted through cell-to-cell contact. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied, the mechanisms facilitating the encounter between an infected cell and a target cell remain unknown. We postulated that the infected cells could behave as a source of chemoattractant, thus recruiting target cells. In 2012, Trindade et al. showed that PBMCs from HTLV-1 infected individuals (HTLV-1 asymptomatic carrier and HAM/TSP patients) could secrete higher levels of leukotriene B4 (LTB4), a potent chemoattractant, than cells from healthy donors. We proposed that, although T cells purportedly secrete no LTB4, LTB4 could be secreted by HTLV-1 infected lymphocytes and facilitate cell-to-cell contacts and viral transmission. We showed by ELISA that HTLV-1 infected lymphocytes (both primary CD4+ T cells and chronically infected cell lines) secrete LTB4. By cell transduction with lentiviral vectors encoding Tax, we suggest that HTLV-1 induced LTB4 secretion is a consequence of Tax-induced cytosolic phospholipase A2 (cPLA2) over expression. Blocking LTB4 secretion (with diverse specific inhibitors of the leukotriene pathway) prevented the recruitment of potential target cells, as well as the formation of cell-to-cell contacts. In conclusion, HTLV-1 diverts the leukotriene pathway and LTB4-mediated chemotaxis facilitates viral propagation.

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