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dc.contributor.authorCastro Filho, Bernardo Galvão-
dc.contributor.authorLeal, Fabio E.-
dc.contributor.authorMenezes, Soraya Maria-
dc.contributor.authorCosta, Emanuela A. S.-
dc.contributor.authorBrailey, Phillip M.-
dc.contributor.authorGama, Lucio-
dc.contributor.authorSegurado, Aluisio C.-
dc.contributor.authorKallas, Esper G.-
dc.contributor.authorNixon, Douglas F.-
dc.contributor.authorDierckx, Tim-
dc.contributor.authorKhouri, Ricardo-
dc.contributor.authorVercauteren, Jurgen-
dc.contributor.authorRaposo, Rui Andre Saraiva-
dc.contributor.authorWeyenbergh, Johan Van-
dc.date.accessioned2019-06-12T11:28:51Z-
dc.date.available2019-06-12T11:28:51Z-
dc.date.issued2018-05-22-
dc.identifier.numberdoi: 10.3389/fmicb.2018.00985pt_BR
dc.identifier.urihttp://www7.bahiana.edu.br//jspui/handle/bahiana/2941-
dc.description.abstractHTLV-1-Associated Myelopathy (HAM/TSP) is a progressive neuroinflammatory disorder for which no disease-modifying treatment exists. Modest clinical benefit from type I interferons (IFN-a/b) in HAM/TSP contrasts with its recently identified IFN-inducible gene signature. In addition, IFN-a treatment in vivo decreases proviral load and immune activation in HAM/TSP, whereas IFN-b therapy decreases tax mRNA and lymphoproliferation. We hypothesize this “IFN paradox” in HAM/TSP might be explained by both cell type- and gene-specific effects of type I IFN in HTLV-1-associated pathogenesis. Therefore, we analyzed ex vivo transcriptomes of CD4+ T cells, PBMCs and whole blood in healthy controls, HTLV-1-infected individuals, and HAM/TSP patients. First, we used a targeted approach, simultaneously quantifying HTLV-1 mRNA (HBZ, Tax), proviral load and 42 host genes with known antiretroviral (anti-HIV) activity in purified CD4+ T cells. This revealed two major clusters (“antiviral/protective” vs. “proviral/deleterious”), as evidenced by significant negative (TRIM5/TRIM22/BST2) vs. positive correlation (ISG15/PAF1/CDKN1A) with HTLV-1 viral markers and clinical status. Surprisingly, we found a significant inversion of antiretroviral activity of host restriction factors, as evidenced by opposite correlation to in vivo HIV-1 vs. HTLV-1 RNA levels. The anti-HTLV-1 effect of antiviral cluster genes was significantly correlated to their adaptive chimp/human evolution score, for both Tax mRNA and PVL. Six genes of the proposed antiviral cluster underwent lentivirus-driven purifying selection during primate evolution (TRIM5/TRIM22/BST2/APOBEC3F-G-H), underscoring the cross-retroviral evolutionary imprint. Secondly, we examined the genome-wide type I IFN response in HAM/TSP patients, following short-term ex vivo culture of PBMCs with either IFN-a or IFN-b. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5a/TRIM22/BST2) were significantly up-regulated by IFN-b, but not IFN-a, in HAM/TSP. This was paralleled by a significant decrease in lymphoproliferation by IFN-b, but not IFN- a treatment. Finally, using published ex vivo whole blood transcriptomic data of independent cohorts, we validated the significant positive correlation between TRIM5, TRIM22, and BST2 in HTLV-1-infected individuals and HAM/TSP patients, which was independent of the HAM/TSP disease signature. In conclusion, our results provide ex vivo mechanistic evidence for the observed immunovirological effect of in vivo IFN- b treatment in HAM/TSP, reconcile an apparent IFN paradox in HTLV-1 research and identify biomarkers/targets for a precision medicine approach.pt_BR
dc.language.isoenpt_BR
dc.sourcehttps://www.frontiersin.org/journals/microbiology#pt_BR
dc.subjectHTLV-1, HIV, retrovirus, evolution, interferon, neuroinflammation, multiple sclerosis, transcriptomics.pt_BR
dc.titleComprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-b Response in HTLV-1-Associated Neuroinflammation.pt_BR
dc.title.alternativeFrontiers in Microbiologypt_BR
dc.typeProdução bibliográfica: Artigos completos publicados em periódicospt_BR
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