title: Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes.
abstract: A determinant of human T-lymphotropic virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) development is the HTLV-1-infected cell burden. Viral proteins Tax and HBZ, encoded by the sense and antisense strands of the pX region, respectively, play key roles in HTLV-1 persistence. Tax drives CD4(+)-T cell clonal expansion and is the immunodominant viral antigen recognized by the immune response. Valproate (2-n-propylpentanoic acid, VPA), a histone deacetylase inhibitor, was thought to trigger Tax expression, thereby exposing the latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA on Tax, Gag, and HBZ expressions in cultured lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients. Approximately one-fifth of provirus-positive CD4(+) T cells spontaneously became Tax-positive, but this fraction rose to two-thirds of Tax-positive-infected cells when cultured with VPA. Valproate enhanced Gag-p19 release. Tax- and Gag-mRNA levels peaked spontaneously, before declining concomitantly to HBZ-mRNA increase. VPA enhanced and prolonged Tax-mRNA expression, whereas it blocked HBZ expression. Our findings suggest that, in addition to modulating Tax expression, another mechanism involving HBZ repression might determine the outcome of VPA treatment on HTLV-1-infected-cell proliferation and survival.
authors.affiliation: Laboratoire de Virologie-Immunologie, EA 4537, Centre Hospitalier Universitaire de Fort-de-France, Fort-de-France, Martinique, France.
authors.forename: Gildas
authors.initials: G
authors.lastname: Belrose
authors.forename: Antoine
authors.initials: A
authors.lastname: Gross
authors.forename: Stéphane
authors.initials: S
authors.lastname: Olindo
authors.forename: Agnès
authors.initials: A
authors.lastname: Lézin
authors.forename: Maryvonne
authors.initials: M
authors.lastname: Dueymes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Komla-Soukha
authors.forename: Didier
authors.initials: D
authors.lastname: Smadja
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Luc
authors.initials: L
authors.lastname: Willems
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Mesnard
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Peloponese
authors.forename: Raymond
authors.initials: R
authors.lastname: Césaire
mesh_terms: D016375:Antisense Elements (Genetics) / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D058070:Asymptomatic Diseases; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured / Q000187:drug effects / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016356:Gene Products, tax / Q000096:biosynthesis*; D015750:Genes, gag; D016355:Genes, pX; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D015493:Paraparesis, Tropical Spastic; D011533:Proviruses / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D012191:Retroviridae Proteins; D014635:Valproic Acid / Q000494:pharmacology*; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000096:biosynthesis
chemical_list: D016375:Antisense Elements (Genetics); D050976:Basic-Leucine Zipper Transcription Factors; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D012333:RNA, Messenger; D012367:RNA, Viral; D012191:Retroviridae Proteins; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C060955:p19 protein, Human T-lymphotropic virus 1; C514970:tax protein, Human T-lymphotrophic virus 1; D014635:Valproic Acid; D051548:Histone Acetyltransferases