RESUMEN
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.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Leucotrieno B4/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Femenino , Productos del Gen tax/genética , Productos del Gen tax/metabolismo , Fosfolipasas A2 Grupo IV/genética , Fosfolipasas A2 Grupo IV/metabolismo , Infecciones por HTLV-I/tratamiento farmacológico , Infecciones por HTLV-I/metabolismo , Infecciones por HTLV-I/virología , Interacciones Huésped-Patógeno , Humanos , Indoles/farmacología , Recién Nacido , Células Jurkat , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Ratones Mutantes , FN-kappa B/genética , FN-kappa B/metabolismoRESUMEN
HTLV-1 (Human T-cell Lymphotropic Virus Type 1) is a human retrovirus that infects around 10 million people worldwide. It can be transmitted by sexual contact, transfusion of contaminated blood, and from infected mother-to-child during prolonged breastfeeding. The latter involves viral crossing of the digestive tract. HTLV-1 is the etiological agent of both a lymphoproliferative malignancy, Adult T-cell leukemia/lymphoma, and a chronic inflammatory neuromyelopathy, the Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). TSP/HAM is characterized by HTLV-1-infected lymphocyte infiltration in the central nervous system; these cells cross the blood-brain barrier, an anatomical barrier that normally isolates and protects the central nervous system from blood. In this context, the present review focuses on latest findings and opinions on the interactions of HTLV-1 with the intestinal barrier, as involved in mother-to-child viral transmission, and with the blood-brain barrier, as involved in TSP/HAM pathogenesis.
RESUMEN
UNLABELLED: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. IMPORTANCE: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear. Here, we show that the viral transactivator Tax increases activated leukocyte cell adhesion molecule (ALCAM/CD166) expression. This molecule facilitates the migration of lymphocytes across the BBB endothelium. Targeting this molecule could be of interest in preventing or reducing the development of HAM/TSP.
Asunto(s)
Antígenos CD/metabolismo , Barrera Hematoencefálica , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD4-Positivos/virología , Moléculas de Adhesión Celular Neuronal/metabolismo , Movimiento Celular , Proteínas Fetales/metabolismo , Interacciones Huésped-Patógeno , Virus Linfotrópico T Tipo 1 Humano/fisiología , Linfocitos T CD4-Positivos/química , Línea Celular , Células Endoteliales/química , Productos del Gen tax/metabolismo , Humanos , FN-kappa B/metabolismoRESUMEN
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.