Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-beta Response in HTLV-1-Associated Neuroinflammation

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art_LEAL_Comprehensive_Antiretroviral_Restriction_Factor_Profiling_Reveals_the_Evolutionary_2018.PDF (1.93 MB)
Citações na Scopus
12
Tipo de produção
article
Data de publicação
2018
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
FRONTIERS MEDIA SA
Autores
LEAL, Fabio E.
MENEZES, Soraya Maria
BRAILEY, Phillip M.
GAMA, Lucio
NIXON, Douglas F.
DIERCKX, Tim
KHOURI, Ricardo
Citação
FRONTIERS IN MICROBIOLOGY, v.9, article ID 985, 12p, 2018
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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-alpha/beta) in HAM/TSP contrasts with its recently identified IFN-inducible gene signature. In addition, IFN-alpha treatment in vivo decreases proviral load and immune activation in HAM/TSP, whereas IFN-beta 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-alpha or IFNI,. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5(x/TRIM22/BST2) were significantly up-regulated by IFN-alpha, but not IFN-alpha, in HAM/TSP. This was paralleled by a significant decrease in lymphoproliferation by IFN-beta but not IFN(x 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 IFNtreatment in HAM/TSP, reconcile an apparent IFN paradox in HTLV-1 research and identify biomarkers/targets for a precision medicine approach.
Palavras-chave
HTLV-1, HIV, retrovirus, evolution, interferon, neuroinflammation, multiple sclerosis, transcriptomics
URI
https://observatorio.fm.usp.br/handle/OPI/26966
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MIP
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/49
Artigos e Materiais de Revistas Científicas - LIM/60
Artigos e Materiais de Revistas Científicas - ODS/03