Interferon Beta-1a Treatment in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Case Report

Viana, Graça Maria de Castro; Silva, Marcos Antônio Custódio Neto da; Souza, Victor Lima; Lopes, Natália Barbosa da Silva; Silva, Diego Luz Felipe da; Nascimento, Maria do Desterro Soares Brandão

doi:10.1590/s0036-46652014000500013

Cited by 7 publications

(4 citation statements)

References 13 publications

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“…On the other hand, our study also reveals another parallel between neuroinflammatory disorders HAM/TSP and multiple sclerosis, namely their unique sensitivity to IFN-β over IFN-α. Of note, our results provide mechanistic evidence for the previously described immunovirological and clinical impact observed in vivo with IFN-β therapy in HAM/TSP patients, in an open-label trial (Oh et al, 2005 ), as well as two case reports with remarkable clinical response (Costa et al, 2012 ; Viana et al, 2014 ). This superior antiproliferative effect of IFN-β in HAM/TSP, as compared to IFN-α, parallels our findings in the other major HTLV-1-associated disease, Adult T-cell Leukemia (Dierckx et al, 2017 ).…”

Section: Discussionsupporting

confidence: 81%

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

et al. 2018

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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, IFN-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 IFN-α or IFN-β. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5α/TRIM22/BST2) were significantly up-regulated by IFN-β, but not IFN-α, in HAM/TSP. This was paralleled by a significant decrease in lymphoproliferation by IFN-β, but not IFN-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.

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Section: Discussionsupporting

confidence: 81%

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

et al. 2018

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“…Type I IFNs, including IFN-a and IFN-b, have been used for the treatment of HTLV-1-associated diseases (32,33), suggesting the important role of type I IFNs in HTLV-1 infection. Our findings demonstrated that Ku70 positively regulated HTLV-1-induced IFN-b production.…”

Section: Discussionmentioning

confidence: 99%

Ku70 Senses HTLV-1 DNA and Modulates HTLV-1 Replication

Wang

Kang

Song

et al. 2017

The Journal of Immunology

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Human T lymphotropic virus type 1 (HTLV-1) belongs to the deltaretrovirus family and has been linked to multiple diseases. However, the innate host defense against HTLV-1 is unclear. In this study, we report that the expression of Ku70, a known DNA sensor against DNA viruses, could be induced by HTLV-1 infection in HeLa, PMA-differentiated THP1 cells, primary human monocytes, and human monocyte-derived macrophages. In these cells, the overexpression of Ku70 inhibited the HTLV-1 protein expression, whereas the knockdown of Ku70 promoted the HTLV-1 protein expression. Furthermore, the overexpression of Ku70 enhanced the cellular response to HTLV-1 infection, whereas Ku70 knockdown yielded the opposite effect. Additionally, Ku70 was found to interact with HTLV-1 reverse transcription intermediate ssDNA90. ssDNA90 stimulation induced Ku70 expression and Ku70 promoted ssDNA90-triggered innate immune responses. Finally, HTLV-1 infection enhanced the association between Ku70 and stimulator of IFN genes, suggesting that stimulator of IFN genes was involved in Ku70-mediated host defenses against HTLV-1 infection. Taken together, our findings suggest a new sensor that detects HTLV-1 reverse transcription intermediate and controls HTLV-1 replication. These findings may provide new angles to understand host defenses against HTLV-1 infection and HTLV-1-associated diseases.

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“…Continuous uptake of low-doses of prednisolone by TSP/HAM patients improved their Osame Motor Disability Score both in short-term (less than 3 years) and long-term (more than 3 years) durations of treatment, in comparison to untreated TSP/HAM patients. Because corticosteroid treatments are neither efficient nor tolerated by some patients, alternative treatments using molecules with anti-inflammatory properties, such as cyclosporine A [ 189 ], pentoxifylline [ 190 ], danazol [ 191 ], or antiviral cytokines, such as IFN-α [ 192 , 193 ] or IFN-β [ 194 ], have been developed among others [ 195 ]. Aside from the general motor disability, other TSP/HAM-associated symptoms, such as spasticity, bladder dysfunctions, urinary tract infections, constipation, neuropathic and mechanical pains or erectile troubles are subject to a wide array of drugs [ 123 ].…”

Section: Htlv-1 Treatment and Drug Developmentmentioning

confidence: 99%

HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment

Futsch

Mahieux

Dutartre

2017

Viruses

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Going back to their discovery in the early 1980s, both the Human T-cell Leukemia virus type-1 (HTLV-1) and the Human Immunodeficiency Virus type-1 (HIV-1) greatly fascinated the virology scene, not only because they were the first human retroviruses discovered, but also because they were associated with fatal diseases in the human population. In almost four decades of scientific research, both viruses have had different fates, HTLV-1 being often upstaged by HIV-1. However, although being very close in terms of genome organization, cellular tropism, and viral replication, HIV-1 and HTLV-1 are not completely commutable in terms of treatment, especially because of the opposite fate of the cells they infect: death versus immortalization, respectively. Nowadays, the antiretroviral therapies developed to treat HIV-1 infected individuals and to limit HIV-1 spread among the human population have a poor or no effect on HTLV-1 infected individuals, and thus, do not prevent the development of HTLV-1-associated diseases, which still lack highly efficient treatments. The present review mainly focuses on the course of HTLV-1 infection, from the initial infection of the host to diseases development and associated treatments, but also investigates HIV-1/HTLV-1 co-infection events and their impact on diseases development.

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Interferon Beta-1a Treatment in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Case Report

Cited by 7 publications

References 13 publications

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

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

Ku70 Senses HTLV-1 DNA and Modulates HTLV-1 Replication

HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment

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