Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex vivo and in vivo IFN-β response in HTLV-1-associated neuroinflammation

Fabio E. Leal, Soraya Maria Menezes, Emanuela A.S. Costa, Phillip M. Brailey, Lucio Gama, Aluisio C. Segurado, Esper G. Kallas, Douglas F. Nixon, Tim Dierckx, Ricardo Khouri, Jurgen Vercauteren, Bernardo Galvão-Castro, Rui Andre Saraiva Raposo, Johan Van Weyenbergh

Research output: Contribution to journalArticlepeer-review

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-α/β) in HAM/TSP contrasts with its recently identified IFN-inducible gene signature. In addition, -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 -α or IFN-β. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5α/TRIM22/BST2) were significantly up-regulated by IFN-β, but not -α, in HAM/TSP. This was paralleled by a significant decrease in lymphoproliferation by IFN-β, but not -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.

Original languageEnglish (US)
Article number985
JournalFrontiers in Microbiology
Volume9
Issue numberMAY
DOIs
StatePublished - May 22 2018

Keywords

  • Evolution
  • HIV
  • HTLV-1
  • Interferon
  • Multiple sclerosis
  • Neuroinflammation
  • Retrovirus
  • Transcriptomics

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

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