title: Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth.
abstract: Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4(+) T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4(+) T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4(+) T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser(522). The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4(+)Tax(+) T cells with a high CRMP-2 pSer(522) content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells.
authors.affiliation: 1 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile , Santiago, Chile .
authors.forename: Sebastián
authors.initials: S
authors.lastname: Quintremil
authors.affiliation: 1 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile , Santiago, Chile .
authors.forename: Carolina
authors.initials: C
authors.lastname: Alberti
authors.affiliation: 1 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile , Santiago, Chile .
authors.forename: Matías
authors.initials: M
authors.lastname: Rivera
authors.affiliation: 1 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile , Santiago, Chile .
authors.forename: Fernando
authors.initials: F
authors.lastname: Medina
authors.affiliation: 1 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile , Santiago, Chile .
authors.forename: Javier
authors.initials: J
authors.lastname: Puente
authors.affiliation: 2 Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile , Santiago, Chile .
authors.forename: Luis
authors.initials: L
authors.lastname: Cartier
authors.affiliation: 3 Programa de Virología, ICBM, Facultad de Medicina, Universidad de Chile , Santiago, Chile .|4 Departamento de Virología, Instituto de Salud Pública de Chile , Santiago, Chile .
authors.forename: Eugenio
authors.initials: E
authors.lastname: Ramírez
authors.affiliation: 5 Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus , Ryukyus, Japan .
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: 1 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile , Santiago, Chile .
authors.forename: M Antonieta
authors.initials: MA
authors.lastname: Valenzuela
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002353:Carrier State; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000235:genetics* / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016716:PC12 Cells; D015493:Paraparesis, Tropical Spastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D061251:Primary Cell Culture; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; C093224:CD100 antigen; D017077:Culture Media, Conditioned; D016356:Gene Products, tax; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins