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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 type:Regular Research Grants
Duration: April 01, 2012 - September 30, 2014
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Sabri Saeed Mohamed Ahmed Al-Sanabani
Grantee:Sabri Saeed Mohamed Ahmed Al-Sanabani
Home Institution: Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. 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)

Scientific publications (11)
(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)
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, SEP 2016. Web of Science Citations: 1.
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 MAR 31 2016. Web of Science Citations: 14.
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 FEB 2016. Web of Science Citations: 6.
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, OCT 2015. Web of Science Citations: 7.
PESSOA, RODRIGO; SABINO, ESTER C.; SANABANI, SABRI S. Frequency of coreceptor tropism in PBMC samples from HIV-1 recently infected blood donors by massively parallel sequencing: the REDS II study. VIROLOGY JOURNAL, v. 12, MAY 14 2015. Web of Science Citations: 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.; SANABANI, SABRI S.; RECIPIENT, INT COMPONENT NHLBI. 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, MAY 2015. Web of Science Citations: 7.
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 NOV 17 2014. Web of Science Citations: 13.
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 MAR 31 2014. Web of Science Citations: 26.
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.; KALLAS, ESPER G. 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 FEB 2013. Web of Science Citations: 9.
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, DEC 23 2012. Web of Science Citations: 10.

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