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

Autor(es):Mostrar menos -

Leal, Fabio E. ^{[1, 2]} ; Menezes, Soraya Maria ^[3] ; Costa, Emanuela A. S. ^[4] ; Brailey, Phillip M. ^[1] ; Gama, Lucio ^[5] ; Segurado, Aluisio C. ^[4] ; Kallas, Esper G. ^[4] ; Nixon, Douglas F. ^[1] ; Dierckx, Tim ^[3] ; Khouri, Ricardo ^{[3, 6]} ; Vercauteren, Jurgen ^[3] ; Galvao-Castro, Bernardo ^[7] ; Saraiva Raposo, Rui Andre ^[1] ; Van Weyenbergh, Johan ^[3]

Afiliação do(s) autor(es)

^[1] Inst Nacl Canc INCA, Oncovirol Program, Rio De Janeiro - Brazil

^[2] George Washington Univ, Microbiol Immunol & Trop Med, Washington, DC 20052 - USA

^[3] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Leuven - Belgium

^[4] Univ Sao Paulo, Fac Med, Dept Molestias Infecciosas & Parasitarias, Sao Paulo - Brazil

^[5] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD - USA

^[6] Fundacao Oswaldo Cruz, Inst Goncalo Moniz, Salvador, BA - Brazil

^[7] Escola Bahiana Med & Saude Publ, Salvador, BA - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN MICROBIOLOGY; v. 9, MAY 22 2018.
• Citações Web of Science: 1

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