Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2018 |
| Outros Autores: | , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/27321 |
Resumo: | (Pronex, PVE), KU Leuven (Vaast Leysen Leerstoel voor Infectieziekten in Ontwikkelingslanden) and FWO (grant G0D6817N). This work was partially supported by the National Institutes of Health grant to the District of Columbia Center for AIDS Research, (P30AI087714 and P30AI117970), Fundação de Amparo a Pesquisa do Estado de São Paulo (04/15856-9/EGK and 2010/05845-0/EGK/DFN), CNPq/CAPES 056/2012 (DFN). |
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Leal, Fabio EMenezes, Soraya MariaCosta, Emanuela Avelar SilvaBrailey, Phillip MGama, LucioSegurado, Aluisio CotrimKallas, Esper GeorgesNixon, Douglas FDierckx, TimCunha, Antonio Ricardo KhouriVercauteren, JurgenCastro Filho, Bernardo GalvãoRaposo, Rui Andre SaraivaVan Weyenbergh, Johan2018-07-05T16:33:30Z2018-07-05T16:33:30Z2018LEAL, F. E. et al. Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-β Response in HTLV-1-Associated Neuroinflammation. Frontiers in Microbiology, v. 9, p. 985, 2018.1466-4879https://www.arca.fiocruz.br/handle/icict/2732110.3389/fmicb.2018.00985(Pronex, PVE), KU Leuven (Vaast Leysen Leerstoel voor Infectieziekten in Ontwikkelingslanden) and FWO (grant G0D6817N). This work was partially supported by the National Institutes of Health grant to the District of Columbia Center for AIDS Research, (P30AI087714 and P30AI117970), Fundação de Amparo a Pesquisa do Estado de São Paulo (04/15856-9/EGK and 2010/05845-0/EGK/DFN), CNPq/CAPES 056/2012 (DFN).Instituto Nacional de Câncer. Oncovirology Program. Rio de Janeiro, RJ, Brazil / George Washington University. Microbiology Immunology and Tropical Medicine. Washington, DC, United States.Rega Institute for Medical Research. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium.Universidade de São Paulo. Faculdade de Medicina. Departamento de Moléstias Infecciosas e Parasitárias. São Paulo, SP, Brasil.Instituto Nacional de Câncer. Oncovirology Program. Rio de Janeiro, RJ, Brazil.Johns Hopkins University School of Medicine. Department of Molecular and Comparative Pathobiology. Baltimore, MD, United States.Universidade de São Paulo. Faculdade de Medicina. Departamento de Moléstias Infecciosas e Parasitárias. São Paulo, SP, Brasil.Universidade de São Paulo. Faculdade de Medicina. Departamento de Moléstias Infecciosas e Parasitárias. São Paulo, SP, Brasil.Instituto Nacional de Câncer. Oncovirology Program. Rio de Janeiro, RJ, Brazil.George Washington University. Microbiology Immunology and Tropical Medicine. Washington, DC, United States.George Washington University. Microbiology Immunology and Tropical Medicine. Washington, DC, United States / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.George Washington University. Microbiology Immunology and Tropical Medicine. Washington, DC, United States.Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil.Instituto Nacional de Câncer. Oncovirology Program. Rio de Janeiro, RJ, Brazil.Rega Institute for Medical Research. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium.HTLV-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-α/β) in HAM/TSP contrasts with its recently identified IFN-inducible gene signature. In addition, IFN-α treatment in vivo decreases proviral load and immune activation in HAM/TSP, whereas IFN-β 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-α or IFN-β. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5α/TRIM22/BST2) were significantly up-regulated by IFN-β, but not IFN-α, in HAM/TSP. This was paralleled by a significant decrease in lymphoproliferation by IFN-β, but not IFN-α 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-β treatment in HAM/TSP, reconcile an apparent IFN paradox in HTLV-1 research and identify biomarkers/targets for a precision medicine approach.engNature Publishing GroupHTLV-1HIVRetrovírusEvoluçãoInterferonNeuroinflamaçãoEsclerose múltiplaTranscriptômicaHTLV-1HIVRetrovirusEvolutionInterferonNeuroinflammationMultiple sclerosisTranscriptomicsComprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; 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| dc.title.en.fl_str_mv |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| title |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| spellingShingle |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation Leal, Fabio E HTLV-1 HIV Retrovírus Evolução Interferon Neuroinflamação Esclerose múltipla Transcriptômica HTLV-1 HIV Retrovirus Evolution Interferon Neuroinflammation Multiple sclerosis Transcriptomics |
| title_short |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| title_full |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| title_fullStr |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| title_full_unstemmed |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| title_sort |
Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex Vivo and in Vivo IFN-β response in HTLV-1-Associated Neuroinflammation |
| author |
Leal, Fabio E |
| author_facet |
Leal, Fabio E Menezes, Soraya Maria Costa, Emanuela Avelar Silva Brailey, Phillip M Gama, Lucio Segurado, Aluisio Cotrim Kallas, Esper Georges Nixon, Douglas F Dierckx, Tim Cunha, Antonio Ricardo Khouri Vercauteren, Jurgen Castro Filho, Bernardo Galvão Raposo, Rui Andre Saraiva Van Weyenbergh, Johan |
| author_role |
author |
| author2 |
Menezes, Soraya Maria Costa, Emanuela Avelar Silva Brailey, Phillip M Gama, Lucio Segurado, Aluisio Cotrim Kallas, Esper Georges Nixon, Douglas F Dierckx, Tim Cunha, Antonio Ricardo Khouri Vercauteren, Jurgen Castro Filho, Bernardo Galvão Raposo, Rui Andre Saraiva Van Weyenbergh, Johan |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Leal, Fabio E Menezes, Soraya Maria Costa, Emanuela Avelar Silva Brailey, Phillip M Gama, Lucio Segurado, Aluisio Cotrim Kallas, Esper Georges Nixon, Douglas F Dierckx, Tim Cunha, Antonio Ricardo Khouri Vercauteren, Jurgen Castro Filho, Bernardo Galvão Raposo, Rui Andre Saraiva Van Weyenbergh, Johan |
| dc.subject.other.pt_BR.fl_str_mv |
HTLV-1 HIV Retrovírus Evolução Interferon Neuroinflamação Esclerose múltipla Transcriptômica |
| topic |
HTLV-1 HIV Retrovírus Evolução Interferon Neuroinflamação Esclerose múltipla Transcriptômica HTLV-1 HIV Retrovirus Evolution Interferon Neuroinflammation Multiple sclerosis Transcriptomics |
| dc.subject.en.en.fl_str_mv |
HTLV-1 HIV Retrovirus Evolution Interferon Neuroinflammation Multiple sclerosis Transcriptomics |
| description |
(Pronex, PVE), KU Leuven (Vaast Leysen Leerstoel voor Infectieziekten in Ontwikkelingslanden) and FWO (grant G0D6817N). This work was partially supported by the National Institutes of Health grant to the District of Columbia Center for AIDS Research, (P30AI087714 and P30AI117970), Fundação de Amparo a Pesquisa do Estado de São Paulo (04/15856-9/EGK and 2010/05845-0/EGK/DFN), CNPq/CAPES 056/2012 (DFN). |
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2018 |
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2018-07-05T16:33:30Z |
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2018-07-05T16:33:30Z |
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2018 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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LEAL, F. E. et al. Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-β Response in HTLV-1-Associated Neuroinflammation. Frontiers in Microbiology, v. 9, p. 985, 2018. |
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https://www.arca.fiocruz.br/handle/icict/27321 |
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1466-4879 |
| dc.identifier.doi.none.fl_str_mv |
10.3389/fmicb.2018.00985 |
| identifier_str_mv |
LEAL, F. E. et al. Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-β Response in HTLV-1-Associated Neuroinflammation. Frontiers in Microbiology, v. 9, p. 985, 2018. 1466-4879 10.3389/fmicb.2018.00985 |
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https://www.arca.fiocruz.br/handle/icict/27321 |
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openAccess |
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Nature Publishing Group |
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Nature Publishing Group |
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