| Texto completo | |
| Autor(es): Mostrar menos - |
Leal, Fabio E.
;
Menezes, Soraya Maria
;
Costa, Emanuela A. S.
;
Brailey, Phillip M.
;
Gama, Lucio
;
Segurado, Aluisio C.
;
Kallas, Esper G.
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Nixon, Douglas F.
;
Dierckx, Tim
;
Khouri, Ricardo
;
Vercauteren, Jurgen
;
Galvao-Castro, Bernardo
;
Saraiva Raposo, Rui Andre
;
Van Weyenbergh, Johan
Número total de Autores: 14
|
| Tipo de documento: | Artigo Científico |
| Fonte: | FRONTIERS IN MICROBIOLOGY; v. 9, p. 12-pg., 2018-05-22. |
| 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. (AU) | |
| Processo FAPESP: | 04/15856-9 - Análise prospectiva das características virológicas e imunológicas em indivíduos com infecção recente pelo HIV-1 das cidades de São Paulo e Santos, SP |
| Beneficiário: | Ricardo Sobhie Diaz |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 10/05845-0 - Resposta imune celular em doenças infecciosas e imunodeficiências primárias |
| Beneficiário: | Esper Georges Kallás |
| Modalidade de apoio: | Auxílio à Pesquisa - Pesquisador Visitante - Internacional |