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|Title:||Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-b Response in HTLV-1-Associated Neuroinflammation.|
|Other Titles:||Frontiers in Microbiology|
|Authors:||Castro Filho, Bernardo Galvão|
Leal, Fabio E.
Menezes, Soraya Maria
Costa, Emanuela A. S.
Brailey, Phillip M.
Segurado, Aluisio C.
Kallas, Esper G.
Nixon, Douglas F.
Raposo, Rui Andre Saraiva
Weyenbergh, Johan Van
|Keywords:||HTLV-1, HIV, retrovirus, evolution, interferon, neuroinflammation, multiple sclerosis, transcriptomics.|
|Abstract:||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-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.|
|Appears in Collections:||Artigos Completos Publicados em Periódicos|
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