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Profiling the human T-cells miRNA, REX and tax transcriptomes in the course of HTLV-1 infection using a deep sequencing approach

Grant number: 11/12297-2
Support Opportunities:Regular Research Grants
Duration: April 01, 2012 - September 30, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Sabri Saeed Mohammed Ahmed Al-Sanabani
Grantee:Sabri Saeed Mohammed Ahmed Al-Sanabani
Host Institution: Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers:Ester Cerdeira Sabino

Abstract

The HTLV-1 was the first human retrovirus to be isolated and has been shown to cause a broad spectrum of clinical manifestations including adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraperesis (HAM/TSP). The latency period to induce ATLL can be extremely long (30 to 50 years), indicating that combination/cooperation of specific genetic and viral events are involved in the multi-step evolution of silent infection to full-blown ATLL. The mechanisms responsible of cells transformation to ATLL are not yet fully understood. It is believed that continual viral expression of HTLV proteins, particularly tax, and the abundant proliferation of lymphocytes may increase the probability of inflammation and stimulate cell migration, thus increase the risk of HAM/TSP and other HTLV-1-associated inflammatory diseases. Also, enhanced lymphocyte proliferations would increase the chance of acquiring mutations that could increase the risk of malignant transformation and the development of ATLL. In recent years, in vivo study reveals interesting findings that demonstrate an absence of tax expression in approximately 60% of late leukemia's. These intriguing results raise an important question, what are other factor(s) needed to maintain the leukemic phenotype of ATL cells in the absence of tax? One possible answer for this question might lie in deregulation of cellular miRNAs in ATL transformed cells that permanently changes the cellular regulation of gene expression patterns and maintaining the malignant phenotype independently of tax protein. In this regard, few studies have demonstrated that cells infected with HTLV-1 have different expression levels of human miRNAs, suggesting that tax is responsible for cell transformation and miRNAs for the permanence of the transformed cells. Moreover, these studies also point to the rex gene as a possible attenuator of intracellular antiviral response, acting as a silencer of miRNAs. Against this background, it appeared that measuring miRNAs abundances provides more comprehensive information about the molecules most closely involved in cellular regulation and operation. In this study, we aim to evaluate the expression levels of all human miRNAs in T-cells from HTLV-I asymptomatic carriers, patients with ATLL and patients with HAM/TSP. Our approach to identify potential miRNAs and/or isoforms molecules involves utilizing high throughput sequencing to determine the quantitative analysis of each miRNAs in each group. A comparative analysis of these molecules in each of these diseased and non-diseased states should yield valuable insight into identifying miRNAs and/or isoforms involved with the pathogenesis of both ATLL and HAM/TSP. We also aim to make use of the deep sequencing technology to underscore the importance of assessing t-cell clonality and their association with HTLV-1 proviral load. Deep sequencing of t-cell receptor is potentially useful in tracking monoclonal T cell expansions and enables detection of clonal T cell populations that do not show aberrant cell surface marker. This high-resolution analysis will offers the potential for predicting patients predisposed to ATLL or HAM/TSP. Overall, the results are expected to yield novel data for understanding the ATLL and HAM/TSP disorders associated with HTLV-1 infection. In addition, the novel candidate miRNA that we identify using these sequencing techniques may yield potentially valuable therapeutic targets for HTLV-1 disorders. This approach will allow us to identify potential biomarkers in each clinical entity, search for new miRNAs and/ or isoforms, examine the expression of mRNA for the HTLV- I tax/rex, determine the rate of t cell clonality and their association with HTLV-1 proviral load. (AU)

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Scientific publications (15)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PESSOA, RODRIGO; WATANABE, JAQUELINE TOMOKO; CALABRIA, PAULA; FELIX, ALVINA CLARA; LOUREIRO, PAULA; SABINO, ESTER C.; BUSCH, MICHAEL P.; SANABANI, SABRI S.; RECIPIENT, INT COMPONENT NHLBI. Deep Sequencing of HIV-1 near Full-Length Proviral Genomes Identifies High Rates of BF1 Recombinants Including Two Novel Circulating Recombinant Forms (CRF) 70_BF1 and a Disseminating 71_BF1 among Blood Donors in Pernambuco, Brazil. PLoS One, v. 9, n. 11, . (11/11090-5, 11/12297-2)
PEREIRA DA FONSECA, TAIRACAN AUGUSTO; PESSOA, RODRIGO; SANABANI, SABRI SAEED. Molecular investigation of bacterial communities: Data from two frequently used surfaces in the Sao Paulo Institute of Tropical Medicine. DATA IN BRIEF, v. 8, p. 399-403, . (14/26983-3, 11/12297-2)
PEREIRA DA FONSECA, TAIRACAN AUGUSTO; PESSOA, RODRIGO; SANABANI, SABRI SAEED. Molecular Analysis of Bacterial Microbiota on Brazilian Currency Note Surfaces. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH, v. 12, n. 10, p. 13276-13288, . (11/11090-5, 11/12297-2)
PESSOA, RODRIGO; WATANABE, JAQUELINE TOMOKO; CALABRIA, PAULA; ALENCAR, CECILIA SALETE; LOUREIRO, PAULA; LOPES, MARIA ESTHER; PROETTI, ANNA BARBARA; FELIX, ALVINA CLARA; SABINO, ESTER C.; BUSCH, MICHAEL P.; et al. Enhanced detection of viral diversity using partial and near full-length genomes of human immunodeficiency virus Type 1 provirus deep sequencing data from recently infected donors at four blood centers in Brazil. Transfusion, v. 55, n. 5, p. 980-990, . (11/11090-5, 11/12297-2)
PESSOA, RODRIGO; WATANABE, JAQUELINE TOMOKO; NUKUI, YOUKO; PEREIRA, JULIANA; KASSEB, JORGE; PENALVA DE OLIVEIRA, AUGUSTO CESAR; SEGURADO, ALUISIO COTRIM; SANABANI, SABRI SAEED. Molecular Characterization of Human T-Cell Lymphotropic Virus Type 1 Full and Partial Genomes by Illumina Massively Parallel Sequencing Technology. PLoS One, v. 9, n. 3, . (11/12297-2)
SANABANI, SABRI SAEED; NUKUI, YOUKO; PEREIRA, JULIANA; DA COSTA, ANTONIO CHARLYS; SOARES DE OLIVEIRA, ANA CAROLINA; PESSOA, RODRIGO; LEAL, FABIO EUDES; SEGURADO, ALUISIO C.; KALLAS, ESPER GEORGES; SABINO, ESTER CERDEIRA. Lack of evidence to support the association of a single IL28B genotype SNP rs12979860 with the HTLV-1 clinical outcomes and proviral load. BMC INFECTIOUS DISEASES, v. 12, . (10/08550-1, 11/12297-2)
PESSOA, RODRIGO; DE FREITAS CARNEIRO PROIETTI, ANNA BRBARA; BUSCH, MICHAEL P.; SANABANI, SABRI S.. Identification of a Novel HIV-1 Circulating Recombinant Form (CRF72_BF1) in Deep Sequencing Data from Blood Donors in Southeastern Brazil. GENOME ANNOUNCEMENTS, v. 2, n. 3, p. 2-pg., . (11/12297-2, 11/11090-5)
VALADAO DE SOUZA, DANIELA RAGUER; PESSOA, RODRIGO; NASCIMENTO, ANDREZZA; NUKUI, YOUKO; PEREIRA, JULIANA; CASSEB, JORGE; PENALVA DE OLIVEIRA, AUGUSTO CESAR; DA SILVA DUARTE, ALBERTO JOSE; CLISSA, PATRICIA BIANCA; SANABANI, SABRI SAEED. Small RNA profiles of HTLV-1 asymptomatic carriers with monoclonal and polyclonal rearrangement of the T-cell antigen receptor gamma-chain using massively parallel sequencing: A pilot study. Oncology Letters, v. 20, n. 3, p. 2311-2321, . (14/24596-2, 11/12297-2)
PEREIRA DA FONSECA, TAIRACAN AUGUSTO; PESSOA, RODRIGO; FELIX, ALVINA CLARA; SANABANI, SABRI SAEED. Diversity of Bacterial Communities on Four Frequently Used Surfaces in a Large Brazilian Teaching Hospital. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH, v. 13, n. 2, . (14/26983-3, 11/12297-2)
PESSOA, RODRIGO; LOUREIRO, PAULA; LOPES, MARIA ESTHER; CARNEIRO-PROIETTI, ANNA B. F.; SABINO, ESTER C.; BUSCH, MICHAEL P.; SANABANI, SABRI S.. Ultra-Deep Sequencing of HIV-1 near Full-Length and Partial Proviral Genomes Reveals High Genetic Diversity among Brazilian Blood Donors. PLoS One, v. 11, n. 3, . (11/11090-5, 14/24596-2, 11/12297-2)
PESSOA, RODRIGO; LOPES, MARIA ESTHER; SANABANI, SABRI S.. Genetic Characterization of HIV-1 Subtype D Near-Full-Length Proviral Genomes by Illumina Massively Parallel Sequencing Technology. GENOME ANNOUNCEMENTS, v. 2, n. 3, p. 2-pg., . (11/12297-2, 11/11090-5)
DE SOUZA, DANIELA RAGUER VALADAO; PESSOA, RODRIGO; NUKUI, YOUKO; PEREIRA, JULIANA; MARCUSSO, ROSA NASCIMENTO; DE OLIVEIRA, AUGUSTO CESAR PENALVA; CASSEB, JORGE; DUARTE, ALBERTO JOSE DA SILVA; CLISSA, PATRICIA BIANCA; SANABANI, SABRI SAEED. Identification of miRnas with possible prognostic roles for HAM/TSP. VIRULENCE, v. 14, n. 1, p. 16-pg., . (22/09354-9, 11/12297-2, 14/24596-2)
LEAL, FABIO E.; NDHLOVU, LISHOMWA C.; HASENKRUG, AARON M.; BRUNO, FERNANDA R.; CARVALHO, KARINA I.; WYNN-WILLIAMS, HARRY; NETO, WALTER K.; SANABANI, SABRI S.; SEGURADO, ALUISIO C.; NIXON, DOUGLAS F.; et al. Expansion in CD39(+) CD4(+) Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications. PLoS Neglected Tropical Diseases, v. 7, n. 2, . (04/15856-9, 10/05845-0, 11/12297-2)

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