title: Analyses of HTLV-1 sequences suggest interaction between ORF-I mutations and HAM/TSP outcome.
abstract: The region known as pX in the 3' end of the human T-cell lymphotropic virus type 1 (HTLV-1) genome contains four overlapping open reading frames (ORF) that encode regulatory proteins. HTLV-1 ORF-I produces the protein p12 and its cleavage product p8. The functions of these proteins have been linked to immune evasion and viral infectivity and persistence. It is known that the HTLV-1 infection does not necessarily imply the development of pathological processes and here we evaluated whether natural mutations in HTLV-1 ORF-I can influence the proviral load and clinical manifestation of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). For that, we performed molecular characterization, datamining and phylogenetic analysis with HTLV-1 ORF-I sequences from 156 patients with negative or positive diagnosis for HAM/TSP. Our analyses demonstrated that some mutations may be associated with the outcome of HAM/TSP (C39R, L40F, P45L, S69G and R88K) or with proviral load (P34L and F61L). We further examined the presence of mutations in motifs of HBZ and observed that P45L mutation is located within the HBZ nuclear localization signal and was found more frequently between patients with HAM/TSP and high proviral load. These results indicate that some natural mutations are located in functional domains of ORF-I and suggests a potential association between these mutations and the proviral loads and development of HAM/TSP. Therefore it is necessary to conduct functional studies aimed at evaluating the impact of these mutations on the virus persistence and immune evasion.
authors.affiliation: Centro de Pesquisa Gonçalo Moniz-Fiocruz, Laboratório de Hematologia Genética e Biologia Computacional, Salvador, Bahia, Brazil.
authors.forename: Fernanda Khouri
authors.initials: FK
authors.lastname: Barreto
authors.affiliation: KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Clinical and Epidemiological Virology, Leuven, Belgium.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Khouri
authors.affiliation: Centro de Pesquisa Gonçalo Moniz-Fiocruz, Laboratório de Hematologia Genética e Biologia Computacional, Salvador, Bahia, Brazil.
authors.forename: Filipe Ferreira de Almeida
authors.initials: FFA
authors.lastname: Rego
authors.affiliation: Centro de Pesquisa Gonçalo Moniz-Fiocruz, Laboratório de Hematologia Genética e Biologia Computacional, Salvador, Bahia, Brazil.
authors.forename: Luciane Amorim
authors.initials: LA
authors.lastname: Santos
authors.affiliation: Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, USA.
authors.forename: Maria Fernanda de
authors.initials: MF
authors.lastname: Castro-Amarante
authors.affiliation: Department of General and Experimental Pathology, Medical University in Białystok, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Bialuk
authors.affiliation: Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Pise-Masison
authors.affiliation: Centro de Pesquisa Gonçalo Moniz-Fiocruz, Laboratório de Hematologia Genética e Biologia Computacional, Salvador, Bahia, Brazil; Escola Bahiana de Medicina e Saúde Publica, Salvador, Bahia, Brazil.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Galvão-Castro
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Batiment Lwoff, Institut Pasteur, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.affiliation: Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobson
authors.affiliation: Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, USA.
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.affiliation: Centro de Pesquisa Gonçalo Moniz-Fiocruz, Laboratório de Hematologia Genética e Biologia Computacional, Salvador, Bahia, Brazil. Electronic address: lalcan@bahia.fiocruz.br.
authors.forename: Luiz Carlos
authors.initials: LC
authors.lastname: Alcantara
mesh_terms: D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D017720:Molecular Epidemiology; D009154:Mutation / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics*; D015493:Paraparesis, Tropical Spastic / Q000453:epidemiology* / Q000821:virology*; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D019562:Viral Load
chemical_list: D012367:RNA, Viral
keywords: HAM/TSP; HTLV-1; ORF-1